Preview Applied Organic Chemistry Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry (Surya K. De) (2020)

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Applied Organic Chemistry Applied Organic Chemistry Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry Surya K De Volume Applied Organic Chemistry Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry Surya K De Volume Author Dr Surya K De Supra Sciences San Diego, CA United States Cover Image: © enot-poloskun/Getty Images All books published by Wiley-VCH are carefully produced Nevertheless, authors, editors, and publisher not warrant the information contained in these books, including this book, to be free of errors Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at © 2021 WILEY-VCH GmbH, Boschstr 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages) No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers Registered names, trademarks, etc used in this book, even when not specifically marked as such, are not to be considered unprotected by law Print ISBN: 978-3-527-34785-8 ePDF ISBN: 978-3-527-82815-9 ePub ISBN: 978-3-527-82817-3 oBook ISBN: 978-3-527-82816-6 Typesetting SPi Global, Chennai, India Printing and Binding Printed on acid-free paper 10 v Contents Volume Preface xxiii About the Author xxv About the Book xxvii Acknowledgments xxix List of Abbreviations xxxi Rearrangement Reactions Baeyer–Villiger Oxidation or Rearrangement Mechanism Application Experimental Procedure (from patent US 5142093A) Dakin Oxidation (Reaction) Mechanism Application Experimental Procedure (from patent EP0591799B) Bamberger Rearrangement Mechanism Experimental Procedure (from patent CN102001954B) Beckmann Rearrangement Mechanism Application Experimental Procedure (general) Preparation of Caprolactam (from patent US 3437655A) Benzilic Acid Rearrangement Mechanism Application Experimental Procedure (from patent US20100249451B) Baker–Venkataraman Rearrangement Mechanism 10 Application 10 Experimental Procedure (from patent CN105985306B) 10 vi Contents Claisen Rearrangement 11 Mechanism 11 Application 12 Experimental Procedure (from patent WO2016004632A1) 13 Eschenmoser–Claisen Rearrangement 13 Mechanism 13 Ireland–Claisen Rearrangement 14 Mechanism 14 Johnson–Claisen Rearrangement 15 Mechanism 15 Overman Rearrangement 15 Mechanism 16 Cope Rearrangement 16 Mechanism 17 Application 17 Experimental Procedure (from patent US 4421934A) 17 Curtius Rearrangement 17 Mechanism 18 Application 18 Experimental Procedure (from patent EP2787002A1) 19 Demjanov Rearrangement 19 Mechanism 20 Application 21 Experimental Procedure (from Reference [14], copyright 2008, American Chemical Society) 21 Tiffeneau–Demjanov Rearrangement 22 Mechanism 22 Application 23 Experimental Procedure (from Reference [10], copyright, The Royal Society of Chemistry) 23 Fries Rearrangement 23 Mechanism 24 Application 24 Experimental Procedure (from patent US9440940B2) 25 Favorskii Rearrangement 25 Mechanism 25 Application 26 Experimental Procedure (from patent EP3248959A2) 26 Fischer–Hepp Rearrangement 26 Mechanism 27 Experimental Procedure (general) 27 Hofmann Rearrangement (Hofmann degradation of amide) 28 Mechanism 28 Application 29 Experimental Procedure (from patent CN105153023B) 29 Hofmann–Martius Rearrangement 29 Mechanism 30 Contents Experimental Procedure (from patent DD295338A5) 30 Lossen Rearrangement 31 Mechanism 31 Application 32 Experimental Procedure (from patent EP2615082B1) 32 Orton Rearrangement 32 Mechanism 33 Pinacol–Pinacolone Rearrangement 33 Mechanism 34 Application 34 Experimental Procedure (general) 34 Rupe Rearrangement/Meyer–Schuster Rearrangement 34 Rupe Rearrangement 35 Meyer–Schuster Rearrangement 35 Mechanism 35 Application 36 Experimental Procedure (from patent US4088681A) 36 Schmidt Rearrangement or Schmidt Reaction 36 Mechanism 37 Application 37 Experimental Procedure (from patent WO2009026444A1) 38 Wagner–Meerwein Rearrangement 38 Mechanism 38 Application 39 Wolff Rearrangement 39 Mechanism 39 Alternatively 40 Application 40 Experimental Procedure (from patent US9175041B2) 9175041B2 40 Arndt–Eistert Homologation or Synthesis 41 Mechanism 41 Application 42 Experimental Procedure (from patent US9399645B2) 42 Step 42 Step 42 Zinin Rearrangement or Benzidine and Semidine Rearrangements 42 Mechanism 43 Experimental Procedure (from patent US20090069602A1) 44 References 45 Baeyer-Villiger Oxidation or Rearrangement 45 Dakin Oxidation or Reaction 47 Bamberger Rearrangement 48 Beckmann Rearrangement 48 Benzilic Acid Rearrangement 50 Baker–Venkataraman Rearrangement 51 vii viii Contents Claisen Rearrangement/Eschenmoser–Claisen Rearrangement/Ireland–Claisen Rearrangement/Johnson–Claisen Rearrangement/Overman Rearrangement 52 Cope Rearrangement 53 Curtius Rearrangement 54 Demjanov Rearrangement 56 Tiffeneau–Demjanov Rearrangement 56 Fries Rearrangement 56 Favorskii Rearrangement 58 Fischer–Hepp Rearrangement 58 Hofmann Rearrangement (Hofmann Degradation of Amide) 59 Hofmann–Martius Rearrangement 60 Lossen Rearrangement 60 Orton Rearrangement 61 Pinacol–Pinacolone Rearrangement 62 Rupe Rearrangement/Meyer–Schuster Rearrangement 62 Schmidt Rearrangement or Schmidt Reaction 63 Wagner–Meerwein Rearrangement 64 Wolff Rearrangement 65 Arndt–Eistert Homologation or Synthesis 66 Zinin Rearrangement or Benzidine and Semidine Rearrangements 67 Condensation Reaction 69 Aldol Condensation Reaction 69 Application 70 Experimental Procedure (general) 71 Enantioselective Aldol Reaction (from patent US 6919456B2) 71 Mukaiyama Aldol Reaction 72 Mechanism 72 Application 72 Experimental Procedure (from patent DE102013011081A1) 73 Evans Aldol Reaction 73 Mechanism 74 Application 74 Experimental Procedure (from patent WO2013151161A1) 74 Henry Reaction 75 Mechanism 75 Application 76 Experimental Procedure (from patent US 6919456B2) 76 Preparation of Chiral Catalyst 76 Nitro-Aldol Reaction 76 Benzoin Condensation 76 Mechanism 77 Application 77 Experimental Procedure (from patent DE3019500C2) 78 Claisen Condensation 78 Mechanism 78 Contents Application 79 Experimental Procedure (from patent US9884836B2) 79 Darzens Glycidic Ester Condensation 80 Mechanism 80 Application 81 Experimental Procedure (from patent JP2009512630A) 81 Dieckmann Condensation 81 Mechanism 82 Application 82 Experimental Procedure (from patent US 7132564 B2) 82 Knoevenagel Condensation 83 Mechanism 83 Application 84 Lumefantrine 84 Experimental Procedure (from patent WO2010136360A2) 84 Pechmann Condensation (synthesis of coumarin) (also called von Pechmann condensation) 85 Mechanism 85 Application 86 Experimental Procedure (from patent US7202272B2) 86 Perkin Condensation or Reaction 86 Mechanism 87 Application 88 Experimental Procedure (from patent US4933001A) 88 Stobbe Condensation 88 Mechanism 89 Application 89 Experimental Procedure (from patent US20160137682A1) 90 References 90 Aldol Condensation Reaction 90 Mukaiyama Aldol Reaction 93 Evans Aldol Reaction 96 Henry Reaction 98 Benzoin Condensation 99 Claisen Condensation 101 Darzens Glycidic Ester Condensation 102 Dieckmann Condensation 103 Knoevenagel Condensation 105 Pechmann Condensation 106 Perkin Condensation or Reaction 107 Stobbe Condensation 108 Olefination, Metathesis, and Epoxidation Reactions 111 Olefination 111 Corey–Winter Olefin Synthesis 111 Mechanism 112 Application 112 ix x Contents Experimental Procedure (from patent US5807866A) 112 Horner–Wadsworth–Emmons Reaction 113 Mechanism 113 Application 113 Experimental Procedure (from patent JPWO2015046403A1) 114 Julia–Lythgoe Olefination 114 Mechanism 115 Modified Julia Olefination 115 Mechanism 115 Application 116 Experimental Procedure (from patent CN103313983A) 116 Julia–Kocienski Olefination 117 Application 117 Experimental Procedure (from patent WO2016125086A1) 118 Kauffmann Olefination 118 Mechanism 119 Application 119 Experimental Procedure (from patent WO2014183211A1) 119 Peterson Olefination 119 Mechanism 120 Application 121 Experimental Procedure (from patent WO2017149091A1) 121 Petasis Olefination 122 Mechanism 122 Application 123 Experimental Procedure (from patent US5087790A) 123 Tebbe Olefination 123 Mechanism 123 Application 124 Experimental Procedure (from patent US8809558B1) 124 Wittig Reaction or Olefination 124 Mechanism 125 Application 126 Experimental Procedure (from patent WO2006045010A2) 126 Metathesis 127 Olefin Metathesis 127 Ring-Closing Metathesis 127 Mechanism 128 Experimental Procedure (from patent US20022018351A1) 128 Cross Metathesis 128 Ring-Opening Metathesis 128 Ring-Opening Metathesis Polymerization (ROMP) 129 Asymmetric Epoxidation 129 Sharpless Asymmetric Epoxidation 129 Mechanism 129 Application 130 Favorskii Rearrangement Experimental Procedure (from patent US9440940B2) O AlCl3 O Cl Cl O O 100 °C O O OCH3 HO OCH3 O B A 0.01 mol of 7-(2′ -chloroacetyloxy)-8-methoxycoumarin (compound A) was directly heated in the presence of 0.015 mol aluminum chloride at 100 ∘ C for three hours After cooling and hydrolysis with diluted hydrochloric acid and ethyl acetate extraction, 6-(2′ -chloroacetyl)-7-hydroxy-8-methoxycoumarin (compound B) was obtained after evaporation of the organic phase The yield was 80% Favorskii Rearrangement The Favorskii rearrangement is an organic reaction used to convert an α-haloketone to a rearranged acid or ester using a strong base (hydroxide or alkoxide) In case of cyclic α-haloketone, this reaction gives a ring contracted product [1–21] The reaction is named after its discoverer the Russian chemist Alexei Yevgrafovich Favorskii [1, 2] O NaOH Ph Cl Ph OH O O NaOEt Ph Ph Cl OEt O O O Cl OH NaOH Mechanism O HO H Cl Step O O O Cl Cl OH Step or – H2O Step O OH H O O H Step O OH Step OH 25 26 Rearrangement Reactions Step 1: Abstraction of α-H on the side of the ketone away from the chlorine atom forms an enolate Step 2: SN 2-type reaction and formation of cyclopropanone ring intermediate Step 3: Hydroxide as a nucleophile attacks at the ketone Step 4: Ring opening gives an anion Step 5: Proton transfers from water or solvent gives the final product Application Total syntheses of naturally occurring products (±)-sterpurene [10], (±)-kelsoene [8], tricycloclavulone [11], and (±)-communiol E [17] have been successfully achieved utilizing this reaction Experimental Procedure (from patent EP3248959A2) NaOMe O MeOH MeO Br A O B To a mixture of 2.60 g of α-bromotetramethylcyclohexanone (compound A) (80.4% GC) and 10 g of methanol in a nitrogen atmosphere was added 2.60 g of a 28% solution of sodium methoxide in methanol at room temperature with stirring After stirring at room temperature for two hours, the reaction mixture was heated with stirring under reflux for two hours and cooled to room temperature 24 g of diluted hydrochloric acid was added, and an organic layer and an aqueous layer were separated The separated organic layer was subjected to usual after treatment, i.e washing, drying, and concentration, to obtain 1.81 g of the envisaged methyl-2,3,4,4-tetramethylcyclopentane carboxylate as a yellowish oil (compound B) (33.2% GC, yield: 36%) Fischer–Hepp Rearrangement The Fischer–Hepp rearrangement is an acid-catalyzed conversion of N-alkyl-N-nitrosoanilines to N-alkyl-para-nitrosoanilines [1] This reaction was discovered by the German chemists Otto Philipp Fischer and Eduard Hepp Several new reaction conditions on this reaction have been developed [2–10] R N NO R R NH NH HCl NO + NO Major Minor Fischer–Hepp Rearrangement N NO NH NH HCl NO + NO Minor Major Mechanism H R N NO R NO N H R N R N H Step H Cl Step + NO Cl H Step NO NO R R NH H N Step H NO NO Cl Step 1: Protonation of amino nitrogen atom by HCl Step 2: Formation of nitrosonium ion Step 3: Aromatic electrophilic substitution at para position or intramolecular migration of + NO Step 4: Abstraction of proton by chloride ion and rearomatization gives the final product Experimental Procedure (general) NO NH NH N NO HCl + AcOH NO A B Major C Minor A solution of A (1 g) in acetic acid 20 ml and 35% HCl ml was stirred at room temperature for three hours The AcOH and HCl solution were removed in vacuo 27 28 Rearrangement Reactions The residue was diluted with ice-cold water and neutralized with ammonia followed by extraction with ethyl acetate The organic layer was washed with water, saturated NaHCO3 solution, and brine The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo The residue was purified over silica gel column chromatography (hexane-ethyl acetate) to afford compound B (major) and compound C (minor) Hofmann Rearrangement (Hofmann degradation of amide) The Hofmann rearrangement is a conversion reaction of primary amide to primary amine with one carbon atom less (via the intermediate isocyanate formation) using alkali (NaOH) and halogen (chlorine or bromine) or hypohalite (NaOCl or NaOBr) This reaction is also referred to as the Hofmann degradation of amide [1–26] Br2 O NH2 NaOH R1 O H2O R1 N C O R1 NH2 NH2 NH2 Br2, NaOH H2O Mechanism O R1 O O H N H Step – H2O R1 NH R1 H N Step OH O H Step N Br –H O R1 – Br O R1 N Br Bromoamide Br Br OH Step – Br H H O Step R1 O N C O H H Carbamic acid O R1 N C O H R1 N C O OH Step R1 N C O Isocyanate OH H2O Step R1 NH2 R1 N C O + CO2 (g) Step 1: Hydroxide abstracts an acidic N–H proton Step 2: The anion reacts with bromine to form an N-bromoamide Step 3: Hydroxide abstracts another acidic H atom from N–H OH Hofmann–Martius Rearrangement Step 4: Elimination of bromide and migration of R1 group to nitrogen atom occur simultaneously to form an isocyanate Step 5: Water or hydroxide reacts with isocyanate Step 6: Proton transfer produces a carbamic acid Step 6: Abstraction of proton with hydroxide Step 7: Carbamic acid loses CO2 and after protonation gives the amine product Application Total syntheses of (+)-cepharamine [8], capreomycin IB [16], (−)-epibatidine [12], (+)-phakellstatin, and (+)-dibromophakellstatin [14] have been accomplished using this reaction Experimental Procedure (from patent CN105153023B) Br Br NaOH, Br2 NH2 N H2O N O NH2 B A Aqueous sodium hydroxide was cooled to ∘ C by the dropwise addition of elemental bromine, cooling to not lower than 10 ∘ C, and was added portion-wise to 4-bromo-pyridine carboxamide (compound A); the addition was complete stirring incubated at least one hour and then heated to 65–90 ∘ C (TLC monitored) The reaction mixture was cooled to room temperature, was centrifuged to obtain a crude product, and was crystallized from toluene to give a pure product, 2-amino-4-bromopyridine (compound B) Hofmann–Martius Rearrangement This is a rearrangement reaction of N-alkylarylamine to the corresponding orthoand/or para-arylalkylated aniline under thermal conditions [1–13] R N H NH2 NH2 HCl R + Heat R Me N H NH2 NH2 HCl Me + Heat Me 29 30 Rearrangement Reactions When the catalyst is a metal halide (Lewis acid) used instead of a protic acid, the reaction is referred to as the Reilly–Hickinbottom rearrangement [3] Me N H NH2 NH2 Me ZnCl2 + Heat Me Mechanism R H N Cl H R HCl NH2 H H N R Cl Step Step Step Step NH2 R H NH2 R Cl S N2 NH2 NH2 NH2 R H R R Cl Cl Step 1: Protonation of NH group from HCl Step 2: Nucleophilic substitution reaction Step 3: Aromatic electrophilic substitution reaction Step 4: Deprotonation and rearomatization Experimental Procedure (from patent DD295338A5) NH2 NH2 HN Catalyst + Heat A C B Minor Major In a reactor filled with Y zeolite in H+ form, N-isopropylaniline (compound A) was introduced to produce p-isopropylaniline (compound B) In the reactor, a pressure of 40 bar and a temperature of 375 ∘ C were maintained To adjust and maintain said pressure, a gas mixture of 75% by volume of nitrogen and 25% by volume of hydrogen was used The reactor also contains the aniline obtained during fractionation of the product mixture and also the o- and polyisopropylanilines based on the N-isopropylaniline in threefold amount Lossen Rearrangement In the continuously operating reactor, a volume velocity of dm3 mixture per dm3 of catalyst was set hourly From the mixture leaving the reactor, the aniline was first distilled off; then the o- and p-isopropylanilines were separated from the polyisopropylanilines The o- and p-isopropylaniline were separated by fractional distillation The p-isopropylaniline was obtained in 99% purity and in relation to the fed N-isopropylaniline in a yield of 81% Lossen Rearrangement The Lossen rearrangement is the intramolecular conversion of hydroxamic acids or their O-acetyl, O-aroyl, and O-sulfonyl derivatives into isocyanates under thermal or in the presence of acid or base catalysts [1–3] Isocyanate can be converted to the corresponding primary amine with water Several reaction conditions and mechanistic studies have been investigated on this reaction [4–22] O H+ R1 O R1 N H O N H R1 NH2 H2O OH R2 R1 N C O R1 NH2 O O R1 H2O R1 N C O N OH H O S O O OH R1 N C O CH3 H2O R1 NH2 Mechanism R1 O Step O N H O R2 O – H2O R1 N R2 Step O O R1 N C O – R2CO2– H O H OH Step H O CO2 + R1 N C O Step O H R1 NH Step – H2O Step R1 NH2 R1 N H R1 N C O O H H O H OH 31 32 Rearrangement Reactions Step 1: Abstraction of the proton from the N atom Step 2: Migration of R1 group to the N-atom and elimination of carboxylate Step 3: Hydrolysis of isocyanate and nucleophilic attack by water Step 4: Proton transfer Step 5: Decarboxylation and liberation of carbon dioxide Step 6: Proton transfer and formation of an amine product Application HIV maturation inhibitor BMS-955176 [17] was synthesized using this reaction Total synthesis of the sesquiterpene illudinine [15] was successfully completed utilizing this reaction Experimental Procedure (from patent EP2615082B1) HO Dimethyl carbonate, TBD H N O MeOH O H N O B A The Lossen rearrangement of N-hydroxyundec-10-enamide (A) (20 g, 100 mmol) with dimethyl carbonate (181 g, mol), methanol (8 ml), and triazabicyclodecene (TBD) (2.79 g, 20 mmol) results in the formation of methyl-dec-9-enylcarbamate After purification by column chromatography (hexane/ethyl acetate : 1–7 : 3), 12.8 g of pure methyl-N-dec-9-enylcarbamate (B) was obtained as a colorless oil (yield: 60%) Orton Rearrangement This is a rearrangement reaction of N-chloroanilides to the corresponding orthoand para-chloroanilides in the presence of acid such as HCl This reaction can proceed in the presence of Lewis acid as well as by light Both solvents and nature of substrates have major role for this rearrangement reaction This reaction is useful for the preparation of para-halo anilides [1–17] O O N N Cl H O N HCl H + Cl Cl Major Minor Pinacol–Pinacolone Rearrangement Mechanism O O N Cl N H O O Cl H + Cl NH Step N H Step + Cl2 HCl Cl Step Cl H Cl Cl Step O NH Cl Major product O NH O O H Cl Cl N NH Cl Cl H Cl Minor Step 1: Protonation Step 2: Nucleophilic substitution reaction Step 3: Aromatic electrophilic substitution reaction Step 4: Deprotonation ensures rearomatization and formation of the desired product Pinacol–Pinacolone Rearrangement The pinacol–pinacolone rearrangement is an acid-catalyzed conversion of a 1,2-diol to a carbonyl compound [1–15] The name of this reaction comes as pinacol rearranges to pinacolone OH OH H3C CH3 H3C CH3 H2SO4 H3C H3C H3C O CH3 Pinacolone Pinacol 33 34 Rearrangement Reactions Mechanism If both the –OH groups are not similar, then the one that gives a more stable carbocation participates in the reaction Subsequently, an alkyl group from the adjacent carbon migrates to the carbocation center H OH OH CH3 H3C CH3 H3C Step OH2 OH CH3 H3C CH3 CH3 Step H3C – H2O H3C H3C H3C H3C OH Step CH3 CH3 Step O CH3 H3C H3C H3C H3C H3C O O H CH3 H CH3 CH3 Step 1: Protonation of one hydroxyl group Step 2: Elimination of water and formation of a carbocation Step 3: Migration of one methyl group Step 4: The loss of proton and formation of final product Application Syntheses of several natural products including (±)-furoscrobiculin B [7], protomycinolide IV [6], 13-keto taxoid compounds [11], and sesquiterpene onitin [15] have been accomplished utilizing this reaction Experimental Procedure (general) O HO Ph Ph A OH Ph Acetic acid Ph Reflux Ph Ph Ph Ph B To benzopinacol (1.83 g, mmol) (compound A) in acetic acid (20 ml) was added one crystal of iodine The reaction mixture was stirred at 118 ∘ C until starting material disappeared (TLC monitored) and then cooled to room temperature The white benzopinacolone (compound B) was precipitated, filtered, washed with cold ethanol, and dried Rupe Rearrangement/Meyer–Schuster Rearrangement The acid-catalyzed rearrangement of tertiary alcohols containing a terminal α-acetylenic group (e.g tertiary propargylic alcohols) via an enyne intermediate Rupe Rearrangement/Meyer–Schuster Rearrangement to give the corresponding α,β-unsaturated ketones is called the Rupe rearrangement [1–3] The acid-catalyzed rearrangement of secondary and tertiary propargylic alcohols to the corresponding α,β-unsaturated aldehydes or ketones is referred to as the Meyer–Schuster rearrangement [4] Several protic acids, Lewis acids, and acidic cation exchange resins have been applied on this reaction [5–34] Rupe Rearrangement O OH Acid H2O Meyer–Schuster Rearrangement R1 OH O Acid (protic or Lewis) R2 R3 H2O R3 R2 R1 Mechanism OH H2O OH2 H Step Step Step – H2O H H –H Step Enyne Step O CH3 H H Step H O H OH O H H H Step H H H Step H –H Step 1: Protonation of hydroxyl group makes a better leaving group Step 2: Elimination of water and formation of carbocation Step 3: 1,2-Shift forms an enyne Step 4: Protonation Step 5: Nucleophilic attacks by water to the carbonium ion Step 6: Deprotonation Step 7: Tautomerization Step 8: Proton transfer forms the desired product 35 36 Rearrangement Reactions Application A new steroidal drug was synthesized in large scale (pilot plant) using this reaction [22] O OH H O Experimental Procedure (from patent US4088681A) O OH HCO2H 95 °C A B 16 g of the acetylene alcohol A was added dropwise at 95 ∘ C to 80 ml of 80% strength formic acid The reaction mixture was kept for one hour at this temperature The formic acid was then distilled off under reduced pressure, the residue was taken up in ether, and the ether solution was washed with 10% sodium bicarbonate solution, dried (MgSO4 ), and distilled 6.4 g (corresponding to 40% of theory) of the corresponding β-damascone B (2,2,6-trimethyl-1-(1′ -oxo-3′ -methyl-but-2′ -en-1′ -yl)-cyclohexene) of boiling point 73–76 ∘ C/0.3 mm Hg was obtained Schmidt Rearrangement or Schmidt Reaction The Schmidt reaction or rearrangement is an acid-catalyzed reaction of hydrogen azide with a carbonyl compound such as an aldehyde, a ketone, or a carboxylic acid to give an amine, amide, or nitrile, respectively, after a rearrangement and the loss of a molecule of nitrogen gas [1–24] This reaction is extended with tertiary alcohol or olefin to give an imine The reaction is named after Carl Friedrich Schmidt [1] O R H2SO4, HN3 OH O R1 H2O, heat R NH2 O H2SO4, HN3 R2 H2O, heat R2 N H R1 Schmidt Rearrangement or Schmidt Reaction O R1 H2SO4, HN3 H H2O heat OH R R R R1 H N H + R1 CN O H2SO4, HN3 R N R R R H2SO4, HN3 R R R R R R N R Mechanism O R1 H O R2 OH Step R1 R2 R1 Step H N N N H N H O H H H O H N N N OH2 Step R1 N N N R2 + H3O N N Step R2 R1 O R2 N H R1 Step R N R1 Step R2 N HO –H R2 H2O R1 R1 migration + N2 Step N N N Step 1: Protonation of oxygen atom of the carbonyl compound Step 2: Nucleophilic attack by an azide to the electron-deficient carbonyl carbon atom Step 3: Protonation Step 4: Elimination of water Step 5: R1 group migration and formation of nitrilium ion Step 6: Nucleophilic attack by water and deprotonation Step 7: Tautomerization gives the desired product Application Total syntheses of several natural products such as (+)-sparteine [5], stemona alkaloid (±)-stemonamine [10], lepadiformines A and C [13], (−)-FR901483 [15], (±)-stemonamine [19], and (+)-erysotramidine [20] have been accomplished strategically using this reaction 37 38 Rearrangement Reactions Experimental Procedure (from patent WO2009026444A1) O O MeO NaN3 MeO NH + S TFA-H2O (9:1) S H N MeO S Major A O Minor B C To a solution of A (0.20 g, 1.0 mmol) in TFA-H2 O (5 ml, v/v : 1) was added NaN3 (50 mg, 0.75 mmol) After being stirred at room temperature for 24 hours under nitrogen, same amount of NaN3 was added to the reaction mixture After 42 hours, the reaction mixture was then gently poured into a mixture of ice and solid K2 CO3 and basified to pH ∼10 The aqueous solution was extracted with dichloromethane, and the organic layer was washed with water and brine The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure The title compound was isolated by column chromatography (dichloromethane/ethyl acetate : 1) in 51% yield of B (major product) and 25% of C Wagner–Meerwein Rearrangement The Wagner–Meerwein rearrangement is an acid-catalyzed alkyl group migration of an alcohol to give an olefin with more substituted This is a cationic [1, 2]-sigmatropic rearrangement reaction This reaction has been applied to synthesize complex natural products and drug molecules [3–38] R1 OH R3 R4 R2 H Acid R2 R1 R3 R4 Mechanism R1 O H R3 R4 R2 H H O H Step – H2O R1 H O H R2 R3 R4 Step – H2 O Step R1 H R3 R4 1,2 shift R2 R2 R3 R1 H R4 O H H Step H3O R2 R1 R3 R4 + Wolff Rearrangement Step 1: Protonation of the alcohol with the acid Step 2: Elimination of water forms a carbocation Step 3: A 1,2-shift (R1 group migration) forms a more stable carbocation Step 4: Deprotonation with water gives a more substituted olefin and regeneration of acid catalyst Application H1N1 influenza virus strains [27] and salimabromide antibiotic polyketide [35] have been synthesized using this reaction Talatisamine is a member of the C19 -diterpenoid alkaloid family, exhibits K+ channel inhibitory and antiarrhythmic activities [38], and was synthesized utilizing this reaction Total syntheses of several natural products such as (+)-quadrone [6], guanacastepene A [14], (−)-isoschizogamine [25], and Lycopodium alkaloid (−)-huperzine A [26] have been accomplished utilizing this reaction Wolff Rearrangement The Wolff rearrangement is a conversion of an α-diazoketone to a ketene with the loss of molecular nitrogen accompanying 1,2-rearrangement using a silver oxide catalyst or thermal or photochemical conditions Generally, these ketenes are not stable to isolate These can undergo a nucleophilic attack by water or alcohol or amine to form one carbon homologation of acid or ester or amide (having one carbon more from starting material) The German chemist Ludwig Wolff discovered this reaction in 1902 [1, 2] Several new catalysts or improved reaction conditions have been developed on this reaction [3–21] H N R R1 O R1 NH2 O N2 R Ag2O H H2O C O or heat or light OH R R O Ketene intermediate R2-OH O R R2 O Mechanism O O R N N2 R H N O O R N N Step – N2 R Step CH H C O R Ketene Alpha ketocarbene 39 .. .Applied Organic Chemistry Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry Surya K De Volume Applied Organic Chemistry Reaction Mechanisms and Experimental Procedures in. .. Stille Coupling Reaction (Migita–Kosugi–Stille Coupling Reaction) 349 Sonogashira Coupling Reaction 351 Kumada Cross-Coupling 353 Hiyama Coupling Reaction 355 Liebeskind–Srogl Coupling Reaction. .. Reading 735 Index 737 722 xxiii Preface Organic chemistry is a constantly developing and expanding field of science because of its in? ??nite research and application possibilities Clear understanding