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Heterocycles: Synthesis, Catalysis, Sustainability, and Characterization

Teresa

M.V.D. Pinho E Melo (Editor)

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Heterocycles

Synthesis,Catalysis,Sustainability,andCharacterization

EditedbyTeresaM.V.D.PinhoeMeloandMartaPineiro

Editors

Prof.TeresaM.V.D.PinhoeMelo UniversityofCoimbra CoimbraChemistryCentre(CQC) DepartmentofChemistry

RuaLarga

3004-535Coimbra

Portugal

Prof.MartaPineiro UniversityofCoimbra CoimbraChemistryCentre(CQC) DepartmentofChemistry

RuaLarga

3004-535Coimbra

Portugal

CoverImage: CourtesyofTeresaM.V.D. PinhoeMeloandMartaPineiro

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Preface xi

1HeterocyclicCompoundsinEnantioselectivePhotochemical Reactions 1

NorbertHoffmann

1.1Introduction 1

1.2AsymmetricCatalysiswithChiralTemplates 2

1.3AsymmetricPhoto-EnzymeCatalysis 7

1.4AsymmetricPhotochemicalReactionsinCrystals 9

1.5CrystallineInclusionComplexes 12

1.6InclusioninZeolites 13

1.7MemoryofChirality 14

1.8ConclusionandPerspectives 15 References 16

2HeterocyclesviaDearomatizationReactions 27

AlexeyM.StarosotnikovandMaximA.Bastrakov

2.1Introduction 27

2.2AnnulationofHeterocyclesviaDearomativeCycloadditiontoArenes andHetarenes 28

2.2.1[3+2]Cycloaddition 28

2.2.2[4+2]Cycloaddition 36

2.2.3OtherCycloadditions 41

2.3IntramolecularAdditiontoAromaticDoubleBondsLeadingto Heterocycles 42

2.4DearomativeSpirocyclizations 45

2.5ConclusionandPerspectives 51 Acknowledgments 51 References 51

3StrategiesfortheSynthesisofHeterocyclicMacrocyclesand Medium-SizedRings 59

WilliamP.UnsworthandThomasC.Stephens

3.1Introduction 59

3.2HighDilutionandPseudo-HighDilutionMethods 61

3.2.1TraditionalHighDilution/SlowAdditionMethods 61

3.2.2Solid-SupportedMethods 65

3.2.3PhaseSeparation 65

3.3MethodsDesignedtoImpartMoreFavorableCyclization Conformations 67

3.3.1TheImportanceofConformationonMacrocyclization 67

3.3.2StructuralFeaturestoBiasCyclizationConformation 69

3.3.3TemplatedMacrocyclization 71

3.4Ring-ExpansionMethods 71

3.5Medium-SizedRings:SpecialCases 75

3.6ConclusionsandPerspectives 77 References 78

4OrganocatalysisinSyntheticHeterocyclicChemistry 85 ÁngelCores,MercedesVillacampa,andJ.CarlosMenéndez

4.1Introduction 85

4.2OrganocatalyticSynthesisofFive-MemberedHeterocycles 87

4.2.1PyrrolesandPyrrolidines 87

4.2.2FuranandBenzofuranDerivatives 89

4.3OrganocatalyticSynthesisofSix-MemberedHeterocycles 90

4.3.1Pyridines,Dihydropyridines,andPiperidines 90

4.3.2FusedPyridineDerivatives 98

4.3.3Pyrimidines 101

4.3.4PyranandFusedPyrans 101

4.4OrganocatalyticSynthesisofSeven-MemberedHeterocycles 104

4.4.1DiazepinesandFusedDiazepines 104

4.4.2ThiazepinesandFusedThiazepines 106

4.5OrganocatalyticSynthesisofPolyheterocyclic,Bridged,andSpiro Compounds 107

4.6ConclusionandPerspectives 111 Acknowledgments 111 References 111

5TransitionMetalCatalysisinSyntheticHeterocyclic Chemistry 117

DinaMurtinhoandM.ElisadaSilvaSerra

5.1Introduction 117

5.2Copper-CatalyzedSynthesisofHeterocycles 118

5.2.1FusedHeterocycles 118

5.2.2Five-andSix-MemberedN-andN,N-Heterocycles 120

5.2.3Five-andSix-MemberedN,O-Heterocycles 126

5.3Pd-CatalyzedHeterocycleSynthesis 127

5.3.1NitrogenHeterocycles 128

5.3.2OxygenHeterocycles 135

5.3.3N,O-Heterocycles 140

5.4ConclusionandPerspectives 142 Acknowledgments 142 References 142

6BiocatalyticSynthesisofHeterocycles 159 AlinaNastkeandHaraldGröger

6.1Introduction 159

6.2Three-MemberedRingHeterocycles 160

6.2.1N-Heterocycles 160

6.2.2O-Heterocycles 160

6.2.2.1HalohydrinDehalogenases 161

6.2.2.2FAD-DependentMonooxygenases 162

6.2.2.3Heme-DependentMonooxygenases 164

6.2.2.4Peroxygenases 166

6.3Four-MemberedRingHeterocycles 169

6.4Five-MemberedRingHeterocycles 171

6.4.1N-Heterocycles 171

6.4.1.1AliphaticHeterocycles 171

6.4.1.2Lactams 174

6.4.1.3AromaticHeterocycles 178

6.4.2O-Heterocycles 181

6.4.2.1AliphaticHeterocycles 181

6.4.2.2Lactones 184

6.4.2.3AromaticHeterocycles 190

6.4.3S-Heterocycles 194

6.5Six-MemberedRingHeterocycles 195

6.5.1N-Heterocycles 195

6.5.2O-Heterocycles 203

6.6ConclusionandPerspectives 203 References 203

7MulticomponentSynthesisofHeterocycles 215 CarolinaS.Marques,ElisabeteP.Carreiro,andAntónioP.S.Teixeira

7.1Introduction 215

7.2Three-MemberedRingHeterocycles 216

7.3Four-MemberedRingHeterocycles 219

7.4Five-MemberedRingHeterocycles 222

7.4.1Five-MemberedRingHeterocycleswithOneHeteroatom 223

7.4.2Five-MemberedRingHeterocycleswithTwoHeteroatoms 232

7.4.3Five-MemberedRingHeterocycleswithThreeandFour Heteroatoms 236

7.5Six-MemberedRingHeterocycles 237

7.5.1Six-MemberedRingHeterocycleswithOneHeteroatom 237

7.5.2Six-MemberedRingHeterocycleswithTwoHeteroatoms 243

7.5.3Six-MemberedRingHeterocycleswithThreeHeteroatoms 247

7.6Seven-MemberedRingHeterocycles 249

7.7ConclusionsandPerspectives 253 Acknowledgments 253 References 254

8HeterocyclicCompoundsfromRenewableResources 277 GiuseppeMele,SelmaE.Mazzetto,andDiegoLomonaco

8.1Introduction 277

8.2Three-,Five-,Six-,andSeven-MemberedRingHeterocyclesBasedon CNSL 278

8.2.1Oxiranes(Epoxides) 278

8.2.2Benzoxazines 281

8.2.3Cardanol-BasedLactones 284

8.2.4Cardanol-BasedAmphiphilicHeterocycles 284

8.2.5Fulleropyrolidines 285

8.2.6TriazolesandPyrimidineHybrids 286

8.3PorphyrinsandPhthalocyaninesDerivedfromCardanol-Based Precursors 286

8.3.1SynthesesofPorphyrins(Pps)andPhthalocyanines(Pcs)from Cardanol-BasedPrecursors 286

8.3.2ApplicationsofCardanol-DerivedPorphyrins(Pps)andPhthalocyanines (Pcs) 288

8.3.2.1Langmuir–BlodgettFilms 288

8.3.2.2SuperparamagneticFluorescentNanosystems 289

8.3.2.3CorrosionProtection 289

8.3.2.4OrganicLight-EmittingDiodes(OLEDs) 289

8.3.2.5PhotodynamicTherapy 290

8.3.2.6CompositesSemiconductor@SensitizerforEnhancingPhotocatalytic Processes 290

8.3.2.7Photo-ignitionofCarbonNanotubes/Ferrocene/PorphyrinUnderLED Irradiation 291

8.3.2.8IntercalationofPpsintoVesicularNanosystems 292

8.3.2.9NanomaterialsBasedonFe3 O4 andPhthalocyaninesDerivedfrom CNSL 292

8.4ConclusionsandPerspectives 293 Acknowledgments 293 References 293

9SynthesisofHeterocyclesinNonconventionalBio-based ReactionMedia 301

AntonV.Dolzhenko

9.1Introduction 301

9.2HeterocyclizationsinGlycerol 302

9.2.1SynthesisofFive-MemberedHeterocyclesinGlycerol 303

9.2.2SynthesisofSix-MemberedHeterocyclesinGlycerol 308

9.2.3SynthesisofSeven-MemberedHeterocyclesinGlycerol 312

9.3HeterocyclizationsinLacticAcid 313

9.3.1SynthesisofFive-MemberedHeterocyclesinLacticAcid 313

9.3.2SynthesisofSix-MemberedHeterocyclesinLacticAcid 315

9.4Heterocyclizationsin γ-Valerolactone 317

9.4.1SynthesisofFive-MemberedHeterocyclesin γ-Valerolactone 318

9.4.2SynthesisofSix-MemberedHeterocyclesin γ-Valerolactone 320

9.5Heterocyclizationsin2-Methyltetrahydrofuran 322

9.5.1SynthesisofFive-MemberedHeterocyclesin 2-Methyltetrahydrofuran 323

9.5.2SynthesisofSix-MemberedHeterocyclesin 2-Methyltetrahydrofuran 325

9.6HeterocyclizationsinMiscellaneousUnconventionalBio-based Media 327

9.7ConclusionandPerspectives 330 Acknowledgments 330 References 330

10MechanochemistryinHeterocyclicSynthesis 339 VjekoslavŠtrukilandDavorMargeti´c

10.1Introduction 339

10.2MechanosynthesisofN-Heterocycles 341

10.2.1Five-MemberedRingHeterocycles 341

10.2.2Six-MemberedRingHeterocycles 351

10.2.3Porphyrins 354

10.3MechanosynthesisofO-,S-,andOtherHeterocycles 355

10.3.1Three-MemberedRingHeterocycles 355

10.3.2Five-MemberedRingHeterocycles 356

10.3.3Six-MemberedRingHeterocycles 359

10.3.4Eight-MemberedRingHeterocycles 363

10.4ConclusionsandPerspectives 363 References 364

11FlowChemistry:SequentialFlowProcessesfortheSynthesis ofHeterocycles 371 PedroBrandão,MartaPineiro,andTeresaM.V.D.PinhoeMelo

11.1Introduction 371

11.2FlowSynthesisofHeterocycles 372

x Contents

11.2.1Three-MemberedRingHeterocycles 372

11.2.2Four-MemberedRingHeterocycles 374

11.2.3Five-MemberedRingHeterocycles 374

11.2.4Six-MemberedRingHeterocycles 384

11.2.5Seven-MemberedRingHeterocycles 390

11.3ConclusionsandPerspectives 391

Acknowledgments 391 References 391

12MatrixIsolationinHeterocyclicChemistry 401

JoséP.L.Roque,CláudioM.Nunes,andRuiFausto 12.1Introduction 401

12.2StructuralCharacterization 403

12.3UV-InducedPhotochemicalReactivity 412

12.4ThermalReactivity 424

12.5IR-InducedProcesses 429

12.6TunnelinginHeterocyclicChemistry 435

12.7ConclusionandPerspectives 444 Acknowledgments 445 References 445

13NMRStructuralCharacterizationofOxygenHeterocyclic Compounds 453

RicardoA.L.S.Santos,DianaC.G.A.Pinto,andArturM.S.Silva 13.1Introduction 453

13.2Three-MemberedHeterocyclicCompounds 454

13.3Four-MemberedHeterocyclicCompounds 459

13.4Five-MemberedHeterocyclicCompounds 466

13.5Six-MemberedHeterocyclicCompounds 477

13.6ChromeneandXanthene-RelatedCompounds 494

13.7ConclusionsandPerspectives 505 Acknowledgments 506 References 506

Index 525

Preface

Heterocyclicchemistryplaysacentralroleinorganicchemistry,beingthefieldwith thegreatestimpactintermsofapplications.Heterocyclesarewidelypresentinmany naturallyoccurringcompoundsandareparticularlyrelevantinthepharmaceutical andagrochemicalindustriesbesidesbeingimportantmaterialsinotherindustrial applications.Therefore,itdoesnotcomeasasurprisethatanimpressivenumber ofcontributionsonheterocyclicchemistryappeareachyearaimingatthedevelopmentofnovelandmoresustainablesyntheticmethodologiesandtoachievehigher structuraldiversitytomeetthedemandsofthevariousheterocycles’applications.

Theplanningofthebookhad Synthesis,Catalysis,SustainabilityandCharacterization asthemainguidelines.The SyntheticMethods includechaptersonselected “hottopics”coveringthestate-of-the-artonsyntheticapproachestoheterocycles. Thechoiceofthemeswasbasedontherelevanceofthetransformationswithregard tothehighpotentialalreadydemonstratedandprospectsfornewdevelopments. Theycomprisethefollowingtopics:chiralheterocyclesviaenantioselectivephotochemicalreactions,heterocyclesviadearomatizationreactions,andanoverview ofsyntheticstrategiestowardheterocyclicmacrocyclesandmedium-sizedrings. Specialfocuswasalsogivento CatalyticMethods withchaptersonorganocatalysis, transition-metalcatalysis,andbiocatalysis.

Atpresent,therelevanceofgreenchemistryisjustifiedbytheinclusionofselected topicson Sustainability inthecontextofthesynthesisofheterocycliccompounds. Multicomponentsynthesis,synthesisfromrenewableresources,synthesisinnonconventionalreactionmedia,mechanochemistry,andflowchemistryarecovered.

Thebookincludesachapterontheuseofmatrixisolationspectroscopyasatool forstructural Characterization andforunprecedentedmechanisticinsightson reactionsinvolvingheterocycliccompounds.Thefinalchapterisacomprehensive overviewonoxygenheterocycles Characterization byNMRspectroscopy,withgreat practicalutilityforthoseworkingwiththesescaffolds.

Thebookisaimedatadvanced-levelreadersandspecialistsintheareaofheterocyclicchemistry.Thisincludesresearchersfromacademiaandstudentsofadvanced coursesonOrganicChemistry,MedicinalChemistry,andGreenChemistry,aswell asresearchersinthefieldofFineChemicalIndustry.

xii Preface

Thisfeatureofhavingtopicscoveringcutting-edgeresearchonheterocyclicchemistrywasonlypossibleduetocontributionsfromanoutstandinginternationalteam of30authors,whicharegratefullyacknowledged,making Heterocycles–Synthesis, Catalysis,Sustainability,andCharacterization auniquebookthatwehopewill becomeareferenceintheareaofHeterocyclicChemistry.

UniversityofCoimbra,Coimbra 22March2022

TeresaM.V.D.PinhoeMelo MartaPineiro

HeterocyclicCompoundsinEnantioselectivePhotochemical Reactions

NorbertHoffmann

UniversitédeReimsChampagne-Ardenne,CNRS,ICMR,EquipedePhotochimie,UFRSciences,B.P.1039, Reims51687,France

1.1Introduction

Thepresentchapterdealswithdifferentkeytopics.Heterocycliccompoundsplaya centralroleinmanydomainsofchemistrysuchasthesearchofnewbiologically activecompoundsinpharmaceuticalandagriculturalchemistry[1].Also,many newmaterialssuchassemiconductingcompoundscontainheterocyclicmoieties[2].Inthesedomains,alargestructuraldiversityandmolecularcomplexity ishighlyneeded.Here,traditionalmethodsoforganicsynthesisfindtheirlimits. Photochemicalreactionsextendsuchlimits.Aselectronicexcitationcompletely changesthechemicalreactivityofcompoundsorwholefamilyofcompounds[3], products,whichcannotbesynthesizedbymoreconventionalmethodsbecome accessibleandareofhighinterestforapplicationinthefieldofbioactivecompounds[4,5].Furthermore,theoutcomeofknownreactions,especiallycatalytic reactions,canbeimprovedwhentheyarecarriedoutunderphotochemical conditions.Basedontheenormousquantityofrecentandpastresultsinthefield ofphotochemicalreactions,itmakessensetosubdividechemicalreactionsinto twoclasses:reactionsthatoccurintheelectronicgroundstateandreactionsin whichelectronicexcitationisinvolved.Fromtheeconomicandecologicalpointof view,photochemicalreactionsareparticularlyinteresting,sincemanyofthemcan becarriedoutwithoutanadditionalchemicalreagent.Thephotonisconsidered asatracelessreagent[6,7].Forthesereasons,thesereactionsarenowhighly appreciatedinchemicalandpharmaceuticalindustry[8–10].

Stereoselectivityalsoplaysacentralroleinorganicsynthesis.Biologicalactivity andmaterialpropertiesstronglydependonthestereochemistryofchemical compounds.Soonerorlater,almostallsynthesismethodswillfacethisproblem. Inthepast,photochemicalreactionshavebeenconsideredasbeinginherently stereo-unselective.Itwasthoughtthatthehighenergyuptakebylightabsorption inducesuncontrolledrelaxationprocessesthatleadtounselectivereactionswith largeamountsofdegradationeitherofthesubstratesorthephotoproducts[11].

1HeterocyclicCompoundsinEnantioselectivePhotochemicalReactions

Inthisregard,itmusthoweverbepointedoutthatstereoselectiveandstereospecific photochemicalreactionshavebeenknownfromtheverybeginningofthisresearch area[12,13].Thecontrolleddissipationofthehighelectronicexcitationenergy inphotochemicalreactionsisthereasonforthehighstereoselectivityinsuch reactions[11].Inparticular,photochemicalreactionscanbeconductedenantioselectivelyinchiralsupramolecularstructures[14,15].Enantiopurecompoundsare obtainedindifferentways:theycanbeprepareddirectlyfromotherchiralprecursorssuchasnaturalproducts(“chiralpool”)orbyopticalresolutionusingdifferent typesofchromatographyorcrystallizationtechniques.Asymmetricsyntheses usingchiralauxiliaries,whichareremovedafterthestereoselectivereaction,also provideenantiopurecompounds.Asymmetriccatalysisandenzymaticcatalysis directlyyieldenantioenrichedcompounds.Achiralenantiopureenvironment inasupramolecularstructureorinacrystalmaybetheinductorofchiralityin asymmetricreactions.Inthepresentchapter,methodswillbediscussedleading directlytoenantiopureheterocycliccompoundsviaphotochemicalreactions.

1.2AsymmetricCatalysiswithChiralTemplates

Photochemicalsubstratesmaybecomplexedwithchiralstructuresthatinduce chirality[16].AtypicalexampleisdescribedinScheme1.1[17].Thequinolone derivative 1 carryingapyrrolidinemoietyundergoesanintramolecularcyclization leadingtothespirocyclicindolizidinecompound 6.Thesubstrateiscomplexedwith theenantiopureKempacidderivative(2)viahydrogenbondsbetweentwolactam

Scheme1.1 Enantioselectivesynthesisofaspirocyclicindolizidinecompoundinducedby aphotochemicalelectrontransfer.

1.2AsymmetricCatalysiswithChiralTemplates 3 moieties.Inthisarrangement,thepyrrolidineapproachesthereactioncenter mainlybyonediastereotopichalf-space.Inthiscomplex,theshieldinggroupacts alsoasanaromaticketonesensitizer(sens).Afterphotochemicalexcitationofthe latter,electrontransferfromthetertiaryaminemoietytotheketoneleadsfirsttoa radicalionpair 3 andafterprotontransfertointermediate 4 [18].Thenucleophilic α-aminoalkylradicalattackswith70%ofstereoselectivitytheelectrophilicdouble bondofthequinolonemoiety.Thus,anelectrophilicoxoallylradicalisgenerated affordingthediradicalintermediate 5.Thefinalproduct 6 resultsfromahydrogen transferfromtheketylradicaltotheoxoallylradical.Itmustbepointedoutthatin thepresentcasethisstepisfavoredbecauseitisanintramolecularprocess.Inthese radicalsteps,polareffectsplayanimportantrole[19–21].Inthecorresponding intermolecularstereoselectivereactions,theseeffectscontributeessentiallytothe efficiencyoftheseprocesses[18].Theintermolecularadditionoftertiaryamines toindolonederivativeswithanexocyclicelectron-deficientolefinicdoublebond hasbeencarriedoutwithsimilarKempacidderivatives[22].Inthiscase,however, rutheniumoriridiumcomplexeshavebeenusedasexternalphotoredoxcatalysts thatwereexcitedbyvisiblelightabsorption.

Usingasimilarchiralsensitizer,anintramolecular[2+2]photocycloadditionhas beencarriedoutwithhighenantioselectivity(Scheme1.2)[23].Thequinolone derivative 7 istransformed,undervisiblelightirradiation,intoacomplexpolycyclic compound 8 containingapyrrolidinemoiety.Itmustbepointedoutthatthe same[2+2]photocycloadditionisalsoinducedbyUVirradiationviadirectlight absorptionbutnochiralinductiontakesplace.Itisthereforenecessarytochoose asensitizerthatabsorbsinthevisibledomainofthelightspectrumtoensure enantioselectivity.Thethioxanthonederivative 9 absorbsinthevisiblelightregion andtransferitstripletenergytothecomplexedsubstrate(10).Again,thiscomplexationoccursviahydrogenbondsbetweenthetwolactamsofthesubstrateandthe Kempacidmoietyofthesensitizer.Inthisstructuretheolefinicdoublebondin thesidechainapproachesthereactivecenterofthequinolonealmostonlybyone

Scheme1.2 Constructionofapyrrolidinemoietyusinganenantioselective[2+2] photocycloaddition.Source:AlonsoandBach[23]/JohnWiley&Sons.

1HeterocyclicCompoundsinEnantioselectivePhotochemicalReactions diastereotopichalf-space.Similarasymmetricreactionshavebeenperformedwith 3-alkylquinolonescarryinga4-O alkenesidechain.Inthiscase,tetrahydrofuran moietiesareformed[24].

Thesubstratecanalsobecomplexedtoametalorastrongcoordinatingatom. Insuchacase,chiralityisinducedbyachiralligandsphere[25].Inthiscontext, chiralLewisacid 11 wasusedtocatalyzetheasymmetricintramolecular[2+2]photocycloadditionofthedihydropyridinonederivative 12 (Scheme1.3)[26].Inthis reaction,a δ-valerolactammoiety(13)isformed.BycomplexationwithaLewisacid, theabsorptionmaximumofcompound 12 isshiftedfrom290to350nm.Usingfluorescentlampswithanemission ��max = 366nm,complex 14 wasexcitedalmost exclusivelysincethenoncomplexedsubstrate 12 doesnotabsorblightinthisspectral range.Thus,theformationofracemicproductasbackgroundreactionissuppressed. Inthecomplex 14,theapproachoftheolefintothereactioncenteragainoccursby onediastereotopichalf-space.

Scheme1.3 EnantioselectiveLewisacidcatalysisofanintramolecular[2+2] photocycloadditionreaction.Source:BrimioulleandBach[26]/AmericanAssociationfor theAdvancementofScience.

α,α,α′ ,α′ -Tetraaryl-2,2-disubstituted1,3-dioxolane-4,5-dimethanols(TADDOLs, e.g. 23)arecapableofcomplexingnumeroussubstratesviahydrogenbonds[27]. Whenaphotochemicalsubstrateiscomplexedwithsuchcompounds,chiralitycan beinduced.Undertheseconditions,whentheflavonederivative 15 wasirradiated withthediphenylbutadiene 16,a[2+3]cycloadditiontookplace,leadingto compounds 17 and 18 (Scheme1.4)[28].AfterreductionwithNaBH4 ,compounds 19 and 20 wereisolatedingoodyields.Furthermore,themajordiastereoisomer 19 wasobtainedinhighenantioselectivity,andrecrystallizationledtoalmost enantiopuresamples.Thehighenantioselectivityofthephotochemicalreaction wasexplainedbythestructureofcomplex 21,whichstronglyfavorstheattackofthe olefinbyonlyonediastereotopichalf-space.Interestingly,whenthestericallymuch lessencumberedchiralalcohol 22 wasaddedinsteadoftheTADDOLcompound

Scheme1.4 Asymmetricsynthesisof( )-foveoglinAusingESIPT-promoted[2+3] cycloadditionwithaﬂavonederivative.Source:Wangetal.[28]/JohnWiley&Sons.

23,anefficientchiralinductionwasstillobserved.Thehighenantioselectivity observedwithhydrogenbondcomplexescanalsobeexplainedbythefactthat excitedstateintramolecularprotontransfer(ESIPT)playsakeyroleinthereaction mechanism[29].Infact,itwasshownthatthecycloadditionoccurredatthetriplet stateof 15 andthatmostprobablysingleelectrontransferisinvolved.Compound 19 wastransformedinto(+)-foveoglinA,whichistheenantiomerofanatural product.Thiscompoundfamilyplaysanimportantroleinmedicinalchemistryas theypossessanticancerandantiviralactivities.

Thecyclizationreactionoftwoalkynesandonenitrilefunctionisaconvenient methodforthepreparationofpyridinecompounds[30].Itcanbecarriedoutunder particularmildconditionswhensimpleandinexpensivecobaltcatalystssuchas 24 areused(Scheme1.5)[31].Underirradiationwithvisiblelight,theformation ofthecobaltacyclopentadieneintermediate 25 isaccelerated,andtheadditionof thenitrileleadingtotheintermediate 26 or 27 becomestherate-determiningstep. Theconsumptionofthenitrilesubstratebecomesthefirst-orderreactionstep. Undertheseparticularlymildconditions,avarietyofpyridinederivativeshave beensynthesizedpossessingfragilesubstituents(Figure1.1)[32].Asymmetric catalysiswasalsosuccessfullyperformed.Thecyclopentadienylligandinthe

Scheme1.5 Visiblelight-supportedcobalt-catalyzed[2+2+2]cycloadditionappliedtothe synthesisofpyridines.

Figure1.1 Pyridinesthathavebeensynthesizedundermildconditionsusing photochemicallypromotedcobalt-catalyzed[2+2+2]cycloaddition.

cobaltcatalystwasreplacedbychiralanalogs,bestresultsbeingobtainedwith catalyst 28 (Scheme1.6)[33].Withthisreactionaxialchiralitycanbeefficiently inducedasshownbythetransformationofcompound 29 intonaphthylpyridine 30.Similarreactionshavebeencarriedoutstartingfrom2-alkoxy-1-naphthonitriles 31 usingdifferentchiralcobaltcomplexesascatalysts.Eitherdiineswereused, leadingtotetracycliccompounds 32,or2equivofamonoalkynewereemployed, yieldingthecorrespondingtricyclicproducts 33.Inthispartofthestudy,the chiralcatalysts ent-28, 34, 35, 36,and 37 havealsobeentested.Thestudyof thistypeofchirality,atropisomerism,hasrecentlygainedparticularattentionin photochemistry[34].

Scheme1.6 Visiblelight-supportedasymmetric[2+2+2]cycloadditionusingchiralcobalt catalysts.

1.3AsymmetricPhoto-EnzymeCatalysis

Enzymecatalysisisageneralmethodtoproduceenantiomericallyenrichedorpure compounds.Manysuchtransformationsneedmulti-enzymesystemsthatcomplicatetheapplicationtoorganicsynthesis.Insomecases,however,thereplacement ofoneormoreenzymeactivitiesbyachemicaltransformationfacilitatesthetransformations.Astheytoleratealargevarietyofreactionconditions,photochemical reactionswereefficientlyappliedinthiscontext[35].

TheBaeyer–Villigermonooxygenase(BVMO)asymmetricallycatalyzesthe transformationofketonesintoestersorlactonesinthecaseofcyclicketones (Scheme1.7)[36].Thisenzymecontainsaflavinadeninedinucleotide(E-FADred ) unit,whichreducesmolecularoxygenintohydrogenperoxidecapableofoxidizingtheketonesubstrate.Theoxidizedflavinspecies(E-FADox )isreduced bynicotinamideadeninedinucleotidephosphate(H)(NADPH).Theresulting nicotinamideadeninedinucleotidephosphate(NADP+ )isreducedviaaglucose dehydrogenase-catalyzedreaction.Thissecondenzymeactivitycanbereplacedby addingflavin(FAD)tothereactionmixture.Thereducedformofthenonbound FADred iscapableofreducingtheenzyme-boundE-FADox .Attheexcitedstate, FADox (generatedbyirradiationwithvisiblelight)iseasilyreducedviaelectron transferfromasacrificialelectrondonorsuchasethylenediaminetetraaceticacid (EDTA).

β-D-glucose D-glucono1,5-lactone

Glucose dehydrogenase

BVMO:Baeyer–Villiger monooxygenase NADP+ NADPH

R:Adeninedinucleotide

E-FAD:EnzymeboundFAD

Coproduct

FADox FADred

R:Adeninedinucleotide

E-FAD:EnzymeboundFAD

BVMO:Baeyer–Villiger monooxygenase

Scheme1.7 Replacementoftheglucosedehydrogenasebyasimplephotoredoxcatalytic systembasedonnonboundFAD.

UndertheseconditionstheasymmetricBaeyer–Villigerreactionwascarriedoutwiththeracemic2-phenylcyclohexanone 38 (Scheme1.8)[37].Only the R-enantiomerwasoxidized,andthephenylcaprolactone 39 wasobtained inhighenantioselectivity.Theracemiccyclobutanonederivative 40 hasbeen transformedunderthesameconditions.Interestinglybothenantiomerswere oxidizedbutdifferentoutcomeswereobserved.The α-S-enantiomeryieldsthe bicyclicbutyrolactone 41,whereasthe α-R-enantiomeristransformedintoregioisomer 42.Bothcompoundsareformedinhighenantioselectivity.Compound 41 istheexpectedregioisomerofaBaeyer–Villigerreaction.Dependingonthe stereochemistryofthestartingketone,theenzymeactivityisthereforecapable ofdirectingtheregioselectivityofthereaction[38].Itshouldbepointedoutthat undersuchreactionconditions,hydrogenperoxideisgeneratedinlowstationary concentrationthatreducestheenzymedegradation[39].

Combinedphoto-andenzymecatalysiswasalsocarriedoutwithalcohol dehydrogenases(ADH)[40].TheseenzymesuseNAD(P)H/NAD(P)+ ascofactor[41].Inordertooptimizetheenzymeactivity,thiscofactorsystemmustbe regenerated[42].Oneofthehydroxylfunctionalitiesoftheachiraldiol 43 isdehydrogenatedtoanaldehydebyhorseliveralcoholdehydrogenase(HLADH)with molecularoxygen(Scheme1.9)[43].Cyclizationleadstothelactol 44,areversible step.InaseconddehydrogenationalsocatalyzedbyHLADH,thelactolisoxidized

Scheme1.8 Enzyme-catalyzedenantioselectiveBaeyer–Villigerreactionappliedtothe synthesisoflactones.Source:Hollmannetal.[37]/JohnWiley&Sons.

Scheme1.9 Enantiospeciﬁcoxidationoftheachiraldiol 43 to4-methyl-δ-valerolactone 45 usingaphotobiocatalyticprocess.Source:Rauchetal.[43]/RoyalSocietyofChemistry.

tothe4-methyl-δ-valerolactone 45,obtainedwithcompleteenantioselectivity. Inthesesteps,hydrogenistransferredtoNAD+ andNADHisformed.NAD+ is regeneratedbyhydrogentransfertooxygenleadingtohydrogenperoxide.Thisstep isphotocatalyzedbyflavinmononucleotide(FMN).Theirradiationwascarried outwithblueLED(��max = 465nm).Undersimilarreactionconditionsandusinga flavin-dependent“ene”-reductase,avarietyoflactamshavebeenobtainedinhigh enantioselectivity[44].

Thecombinationofenzymaticreactionswithphotochemical,inparticular photoredoxprocesses,offersnumerousperspectivesfororganicsynthesis[45]. Thiscombinationisaparticularlyefficientapproachinconnectionwithsustainable orgreenchemistry.Astheseprocessesarethebasisofphotosynthesisingreen plants,theyhavebeensuggestedofpotentialrelevanceforasustainablechemical industrybyG.Ciamicianmorethan100yearsago[46].Itwasthebeginningof greenchemistry[47]althoughithasbeenalmostforgottenoverthedecades.

1.4AsymmetricPhotochemicalReactionsinCrystals

Asymmetricsynthesisisoftenbasedonselectionofconformations.Anefficient methodtodothisistocarryoutreactionsatthecrystallinestate.Molecular

1HeterocyclicCompoundsinEnantioselectivePhotochemicalReactions symmetryandcrystallographyarestronglylinked[48].Particularlyimpressive photochemicalreactionshavebeenreportedwithachiralsubstratesthatcrystallize inSohnckespacegroups[49,50].Whenachiralcompoundscrystallizeinthese spacegroups,mostfrequently,oneenantiopureconformerispresentinsuch homochiralcrystals[51,52].

When α-ketoamides 46 areirradicatedatthesolidstate,thehydroxy-β-lactams 47 areobtainedinhighenantioselectivity(Scheme1.10)[53].Afterlightabsorption,a hydrogenatomistransferredfromanisopropylgrouptothe α-ketofunctionleading tothediradical 48.Radicalcyclizationyieldsthefinalproduct 47.Allthesereaction stepsoccurunderconformationalcontrolexertedbythecrystalenvironment. Inmostcases,enantiomericexcesses(ee)werehigherthan90%.Inthecaseof Ar = Ph,thesubstratecrystallizedinthechiralspacegroup P21 21 21 [54].Irradiation ofthehomochiralcrystalsyieldsproduct 47 (Ar = Ph)in93%ee,whichcrystallized inthesamespacegroup P21 21 21 .Bothenantiomershavebeenselectivelyprepared choosingthecorrespondinghomochiralcrystalsofthesubstrate.Undersimilar conditionstheachiral α,β-unsaturatedthioamide 49 wastransformedintothe thio-β-lactam 50 [55].Afterphotochemicalexcitation,ahydrogenwastransferred fromoneofthebenzylpositionsintothe β-positionofthecyclohexenemoiety(51). Radicalcombinationyieldsthefinalproduct 50.Thestartingproductcrystallizedin the P21 spacegroup,andwhenhomochiralcrystalswereirradiated,oneenantiomer of 50 wasobtainedinhighenantiomericexcess.Itisnoteworthythat,when compound 49 wasirradiatedinsolution,thesameproduct 50 wasisolatedbutas aracemicmixturealongwithsideproducts[56].Variousotherexamplesofthis approachtochiralcompoundshavebeenreported[57].

Scheme1.10 Synthesisof β-lactamsusingabsoluteasymmetricsynthesiswith homochiralcrystalsoftheachiralsubstrates.Eachenantiomerhasbeenselectively producedfromthecorrespondinghomochiralcrystalofthesubstrate.

Thismethodfortheproductionofonlyoneenantiomerwithoutexternalchiral inductionispartofabsoluteasymmetricsynthesis.Usingparticularcrystallization methods,e.g.seedingcrystallizationwiththedesiredhomochiralcrystal,the achiralstartingcompoundcanbeselectivelytransformedintoonlyoneofthe homochiralcrystals[58].Itshouldfurtherbepointedoutthatsuchsolid-statephotochemicalreactionscanalsobecarriedoutonlargerscalewhensuspensionsare irradiated[59].

1.4AsymmetricPhotochemicalReactionsinCrystals 11

Acertaincontrolofthecrystalsymmetrycanbeobtainedbyattachinga homochiralelementtothesubstrate.Inthiscase,thenumberofpossiblespace groupsisreducedto65(Sohnckegroups).Adefinedchiralenvironmentisthus createdaroundthephotochemicalsubstrate[48–51].Inordertoobtainenantiomericallypureorenrichedphotochemicalproducts,thechiralelementshouldnotbe covalentlybondedtothephotochemicalsubstrate[60].Inthiscontext,ammonium saltsofchiralaminesand α-ketoamide 52 carryingacarboxylatefunctionhave beenprepared,andthecrystallinephasewasirradiated(Scheme1.11)[61].In mostcases,theresultinghydroxyl β-lactams 53 havebeenobtainedinhighyield andenantioselectivity.Theoxooxazolidinederivatives 54 wereformedinminor amounts.Bothenantiomersofcarboxylates 53 or 54 havebeenobtainedasmajor stereoisomersdependingontheconfigurationofthechiralammoniumcation.The absoluteconfigurationofthecarboxylateshasnotbeendeterminedinthisstudy.

Scheme1.11 Synthesisof β-lactamsbyirradiationofcrystallinechiralammoniumsalts.

Source:Natarajanetal.[61]/AmericanChemicalSociety.

Asimilarnorbornene 55 derivativehasbeentransformedunderthesameconditions(Scheme1.12)[62].Uponirradiation,thecarbonylisaddedtothealkene functionleadingtothetriplet1,4-diradicalintermediate 56,whichisatypicalintermediateofthePaternò–Büchireaction[63].SuchintermediatesmayundergoC—C bondformationleadingtooxetanes.BondcleavageofthenewlyformedC—Obond (b)canalsotakeplaceregeneratingthestartingcompound.Thisreactionstepplays akeyroleinthestereoselectivePaternò–Büchireactioninsolution[11,64].However,inthepresentcase,aC—Cbond(a)ofthenorbornenemoietyiscleaved, yieldingthefinalproduct 57,abicyclicdihydrofuranderivative.Inmostcases,high stereoselectivitywasobserved.Thereactionisaphoto-Claisenrearrangement[65] withintersystemcrossingtakingplace.

Scheme1.12 Asymmetricphoto-Claisenrearrangementbyirradiationofcrystallinechiral ammoniumsalts.Source:Xiaetal.[62]/AmericanChemicalSociety.

1.5CrystallineInclusionComplexes

Aspointedoutearlier,TADDOLsareauxiliariesthatefficientlyinducechiralitywithoutbeingcovalentlybondedtothereactingmolecule[27].Using co-crystallizationofthesecompoundswithsubstratesofphotochemicalreactions isaninterestingstrategyforasymmetricsynthesis[66,67].CrystalsofTADDOLs arehoststructureswithcavitiesthatcanbefilledbyguestmolecules.When co-crystallizedwithaTADDOLderivativeina1:1ratio,thefuroicacidamide 58 undergoesenantioselectivelyphotocycloadditionyieldingthequinolinonecompound 59 (Scheme1.13)[68].Duetoitspolarmesomericstructure 60,theamide constitutesa6π systemwithbenzeneandfuranmoieties.Therefore,itundergoes conrotatoryphotocyclizationleadingto 61.Thefinalproduct 59 isformedviaa tautomerizationstep.Thesamereactionwascarriedoutwiththeacrylanilide derivative 62 (Scheme1.13).Co-crystalsofa1:1ratiowiththesameTADDOL havebeenirradiated.Again,thequinolinonecompound(63)wasobtainedinhigh enantiomericexcess.Guestmoleculescaninteractprincipallyintwodifferentways withtheTADDOLhostmatrix.Theycanapproachthehostmoleculeswiththeir polarface,whichmayleadtotheformationofhydrogenbonds.Thiswasobserved forthefuroicacidamide 58 (Figure1.2a).Guestmoleculesmayalsointeractwith thearylsubstituentsoftheTADDOLs.Insuchcases,vanderWaals, π–π-stacking,or

Scheme1.13 PhotocyclizationinTADDOLco-crystalsyieldingquinolonesinhigh enantioselectivity.Source:Todaetal.[68]/AmericanChemicalSociety.

Figure1.2 X-raystructuresofcompound 58 (a)and 62 (b)in1:1co-crystalswitha TADDOL(compareScheme1.13).

edge-to-faceinteractions[69]canbeobserved.Thismaybethecaseinthereaction ofcompound 62 (Figure1.2b).

Numerousphotochemicalreactionshavebeenperformedusingcyclodextrins inclusioncomplexes[15,70].Inwatersolution,cyclodextrinsformsuchcomplexes withavarietyoforganicmolecules.However,inmanycaseswhen β-cyclodextrin isused,theinclusioncomplexesarelesssoluble,andthecorrespondingsuspensions,powders,orfilmsareirradiated.Inthiscontext,asuspensionofthe1:1 complexof β-cyclodextrinandtheazepinone 64 hasbeenirradiatedwithUVlight (Scheme1.14)[71].Thephotochemicalproduct 65 washydrogenated,andthe correspondingbicyclic γ-butyrolactam 66 wasisolatedingoodyieldsandmoderate enantioselectivity.Similarresultshavebeenobtainedwhenfilmsoftheinclusion complexwereirradiated.Whenthephotochemicalreactionof 64 inthepresence of β-cyclodextrinwascarriedoutinsolution,followedbyhydrogenation, 66 was isolatedasaracemicmixture.Obviously,undertheseconditions,noinclusionof 66 takesplace.

-Cyclodextrin

Scheme1.14 Photocyclizationofthedihydroazepinone 64 aspartofaninclusion complexwith β-cyclodextrin.Source:Mansouretal.[71]/AmericanChemicalSociety.

1.6InclusioninZeolites

Zeolitesareinorganiccrystallineporousmaterialsthatabsorbsmall-or medium-sizedmoleculesdependingonthecavitysize[72].Theyarefrequently usedascatalysts.Concerningphotochemicalreactions,theyhavebeenusedasa

1HeterocyclicCompoundsinEnantioselectivePhotochemicalReactions

hoststructurefororganicmolecules[73,74].Thephotocyclizationofpyridones 67 tothebicyclic β-lactams 68 hasbeenperformedinsupercagesofMYzeolites,where Maredifferentalkalimetalions(Scheme1.15)[75].Inordertocreateachiral environment,inclusionintothesupercagesofMYzeoliteof( )-norephedrineor ( )-ephedrinetogetherwiththesubstrate 67 wascarriedout.Inordertoassure maximuminteractionwiththechiralinductor,theaminoalcoholswereusedin a10-foldexcess.IncasesoflargersubstituentsR,thebicyclic β-lactams 68 have beenobtainedwithenantiomericexcessesupto53%.Theconfinementofthe non-covalentlybondedchiralinductorwiththepyridonesubstratesreducesthe numberofconformers.Theproximityofthechiralinductordirectsthisselection inanenantioselectiveway.Itmustbepointedoutthatwhenthesamereactions werecarriedoutinsolution,almostnochiralinductionwasobserved.Thereaction wasalsoperformedwithpyridonesubstratesinwhichchiralaminederivatives werecovalentlybonded.Insuchcases,significantdiastereoselectivitywasobserved whencompoundswereabsorbedbyYzeolites.

Scheme1.15 Photochemicaltransformationofpyridones 67 tobicyclic β-lactams 68 co-absorbedwithchiralaminoalcoholsinYzeolites.Source:Sivasubramanianetal.[75]/ RoyalSocietyofChemistry.

1.7MemoryofChirality

Inmanystereoselectivereactions,thechiralinformationistransferredfromachiral center,forexample,achiralcarbonatom,tothereactioncenter[76].Theresulting productsareformedwithdiastereoselectivity.Insomecases,however,suchachiral centerisdestroyed,andthechiralinformationisconserved(memoryofchirality) inmoreorlessstableconformersorothernon-covalentinteractions.Inthisway, suchreactionsbecomestereo-orenantioselective.Suchphenomenaarepartof chiralmemoryeffects[77,78].Inthiscontext,theprolinederivative 69 hasbeen irradiatedinanacetone/watermixture(Scheme1.16)[79].Undertheseconditions, sensitizationoccursviatripletenergytransferfromphotochemicalexcitedacetone to 69.Intramolecularelectrontransferoccursfromthecarboxylatefunctionality tothephthalimidemoiety(70).Immediatedecarboxylationtakesplaceandan α-aminoalkylradical(71)isgenerated.Inthisreactionstep,thechiralinformation attheformerprolinemoietyislost.Radicalcyclizationleadstothefinalproduct

Scheme1.16 Observationofamemoryofchiralityeffectinadecarboxylative photocyclization.Source:Griesbecketal.[79]/JohnWiley&Sons.

72 withhighenantioselectivity.Itmustbepointedoutthatthechiralinformation wasconservedinrelativelyrigidconformationsandtransferredwithinversionof configuration.Thiseffectisexplainedbythefactthatthespinmultiplicitychanges inthisstep.Thetripletdiradical 73 istransformedintothefinalproductinitssinglet state 74.Radicalcombinationandintersystemcrossingconcomitantlyoccurwhen theradicalcarryingporbitalsinthediradicalareorthogonallyorientedasdepicted instructure 73 [80].Suchanarrangementincreasesspin–orbitcoupling.Asshown forthepresentandotherexamples,suchaninteractionhasasignificantimpacton thestereoselectivityofthesereactions[81].Inasimilarelectrochemicalreaction, whichtakesplaceatthesingletgroundstate,almostthesameenantioselectivity wasobservedbutwithretentionofconfigurationatthepyrrolidinemoiety[78,82]. Memoryofchiralityeffectshavebeenobservedinavarietyofphotochemical reactionsinvolvingradicalintermediates[83].

1.8ConclusionandPerspectives

Enantioselectivesynthesisofheterocycliccompoundsplaysanimportantrolein manydomainssuchasthesearchofnewbiologicallyactivecompoundsforusein medicineoragricultureorforthepreparationofnewmaterials.Photochemicalreactionssignificantlycontributetothisresearchfield.Currently,template-supported ororganometalliccatalysisisintensivelyinvestigatedwithconsiderableimpactin photoredoxcatalysisandphotosensitization[84,85].Enzymecatalysisrepresent anefficientmethodforthepreparationofenantiopurecompounds,amongthem manyheterocycliccompounds.Photochemicalreactionscansimplifythecatalytic systems.Inmanycases,theuseofcoenzymeshasbeenreplacedbysimplephotochemicalprocesses.Solid-statephotochemistryisanefficientmethodtocontrolthe equilibriumofconformersinanenantioselectiveway.Consequently,manyofsuch

1HeterocyclicCompoundsinEnantioselectivePhotochemicalReactions

reactionsarecarriedoutwithhighorcompleteenantioselectivity.Thisresearch domainprovidesinterestingperspectivesformaterialscience.Photochemistry ofheterocycliccompoundsalsocontributestobasicunderstandingofchemical reactivity.Memoryofchiralityisobservedinsomeofthesereactions.Forexample, theinfluenceofspin–orbitcoupling,theconformationalrigidityonenantioselectivity,hasbeendiscussedinthiscontext.Itshouldalsobepointedoutthat supramolecularstructures[14]orsupramolecularcatalysis[86]playakeyrolein mostofthesereactions.Amongthereactiondiscussedinthischapter,asymmetric photoredoxcatalyticreactionsandphotochemicallymodifiedenzymaticreactions arecertainlythemostattractivemethodsforapplicationinorganicsynthesis.Inthe contextofsustainablechemistry,photochemicalreactionwithcrystallinesubstrate isparticularlyinterestingsincenosolventisneeded[66,87].

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