Carbon-carbon bond-forming reactions : insertion, olefination and nucleophilic substitution of hydrogen in arenes

108 Pages·1997·3.9 MB·English

by  Toader, Dorin

CARBON-CARBONBOND-FORMINGREACTIONS:
INSERTION,OLEFINATIONAND
NUCLEOPHILICSUBSTITUTIONOFHYDROGENINARENES
By
DORINTOADER
ADISSERT\TIONPRESENTEDTOTHE GRADUATE SCHOOL
OFTHE UNIVERSITYOFFLORIDAINPARTIAL FULFILLMENT
OFTHE REQUIREMENTS FORTHE DEGREE OF
DOCTOR OFPHILOSOPHY
UNIVERSITYOFFLORIDA
1997
mydaughterOanaDanielaandmysonAndreiwithlove
ACKNOWLEDGMENTS
I want to express my deepest gratitude to my supervisor. Professor Alan R.
Katritzky,forhisguidanceandpermanentencouragement.Hisstronginfluencemoldedthe
wayInowperceivethecontemporaryorganicchemistry.
I would like to express sincere thanks to the members of my supervisory
committee.Dr.LisaMcElwee-White,Dr.WilliamR. Dolhier,Jr., Dr.JohnR. Reynolds,
Dr. Nicholas S. Bodor, and Dr. Kathryn Williams for their time spent and helpful
suggestions.
IwouldliketogivemyspecialthankstoDr. LinghongXiefor her permanent
challengeandsupport,Dr.JulianR.Levellforhissuggestionsandhelp,andDr.Jinlong
Jiangforhisguidance.
SpecialthanksgotomyteachersattheUniversityofFloridaespeciallytoDr.Merle
A. Battiste for his challenging organic synthesis class and Dr. Robert Kennedy for
revealingthescienceofseparation.
IamgratefultoMs.DianaAsianforherhelpduringtheseyearsandsupportwhen
nothingworkedasexpectedandforassistanceduringtheeditingofthiswork.
Ithasbeenauniqueexperienceworkingwithinthe Katritzky Research Group.
Thesememorieswillalwaysremainwithme.
ill
TABLEOFCONTENTS
cage
ACKNOWLEDGEMENTS
iii
ABSTRACT vi
CHAPTERS
1 GENERALINTRODUCTION 1
2 GENERALANDEFFICIENTINSERTIONSOFCARBONS
CARRYINGAR\LANDHETEROARYLGROUPS:SYNTHESISOF
ALPHA-ARYL-ANDALPHA-HETEROARYL-SUBSTITUTED
KETONES 4
Introduction 4
ResultsandDiscussion 5
Conclusion 15
ExperimentalSection 15
3 PETERSONOLEHNATIONWITHBENZOTRIAZOLE
STABILIZEDANIONS 25
Introduction 25
EfficientTransformationsofAldehydesandKetonesintoOne-Carbon
HomologatedCarboxylicAcids 25
ExperimentalSection 29
4 MASKEDALPHA-ARYLALKENYLLITHIUMREAGENTSFOR
SYNTHESESOFFUNCTIONALIZEDMONOSUBSTITUTEDAND
1,1-DISUBSTITUTEDETHYLENES 35
Introduction 35
ResultsandDiscussion 36
ExperimentalSection 42
5 VICARIOUSNUCLEOPHILICSUBSTITUTIONOFHYDROGEN
WITHBENZOTRIAZOLEBEARINGANIONS 58
Introduction 58
FirstGeneralSynthesisof/7-(Nitroaryl)diarylmethanesviaVicarious
NucleophilicSubstitutionofHydrogen 59
NewSynthesisof/j-Nitrophenyl-aryl-ketones 65
ExperimentalSection 67
iv
6 PERFORMANCEFLUIDSASANINERTMEDIUMFORTHE
PREPARATIONOFBENZOIRIAZOLEDERIVATIVES 78
Introduction 78
BenzotriazoleAdductsofAldehydeswithAmidesandAmines 79
SynthesisofA^-[2-(Benzotriazolyl)ethyl]-A^-methyl-formamide 84
Conclusions 86
Exp)erimental Section 86
7 CONCLUSIONS 89
REFERENCES 90
BIOGRAPHICALSKETCH 99
V
AbstractofDissertationPresentedtotheGraduateSchool
oftheUniversityofFloridainPartialFulfillmentofthe
RequirementsfortheDegreeofDoctorofPhilosophy
CARBON-CARBONBOND-FORMINGREACTIONS:
INSERTION,OLEFINATIONAND
NUCLEOPHILICSUBSTITUTIONOFHYDROGENINARENES
By
DORINTOADER
August,1997
Chairman: AlanR.Katritzky,FRS
MajorDepartment: Chemistry
1-Arylmethylbenzotriazoles, 1-methoxymethylbenzotriazole and l-(diarylmethyl)
benzotriazolesareexcellentcarbon-carbonbondformingreagentswherebenzotriazoleacts
asbothanactivatortoprotonlossandasaleavinggroup.
Anions formed from the lithiation of a variety of 1-arylmethyl- and 1-
heteroarylmethyl-benzotriazolesundergoadditiontoaliphaticandaromaticaldehydes,and
cyclicandacyclicketones.SubsequentinsituthermalreaiTangemenLsoftheintermediates
inthepresenceofzincbromideprovidedawidevarietyofone-carbonchain-extendedor
ring-expandeda-aryl-anda-heteroarylsubstitutedketonesinmoderatetoexcellentyields
withexcellentregioselectivityinmostcases.Substituenteffectsontherelativemigration
rateswereinvestigatedintheinsertionreactionsofl-(4-methoxybenzyl)benzotriazolewith
benzophenones. The small and negative Hammett p+ value (-0.92) suggests that the
rearrangementsproceedviaearly,reagent-like,electrondeficienttransitionstates.
VI
Peterson olefination of aldehydes and ketones with the
trimethylsilyl(methoxy)(benzotriazol-l-yl)methyl anion afforded l-(benzotriazol-l-yl)-l-
methoxy-l-alkenes which were treated without isolation with zinc bromide and
hydrochloricacid,toyieldthecorrespondingone-carbonhomologatedcarboxylicacidsin
goodoverallyields.
The vicinal elimination of silicon from 2-benzotriazolylethylsilanes provides a
versatilemethodfortheintroductionof1-arylethenylmoietiesintoorganicmolecules.The
2-benzotriazolylethylmoietiesactasmasked 1-arylethenylunitsthatcanbetransformed
intothecorresponding alkene when needed. The vicinal elimination ofsilicon can be
accomplishedbyseveralprotocols, includingpyrolysis, [l,4]-Brookreairangement,and
fluoride ion induced P-elimination. Examples are documented illustrating potentially
general methods for the preparation of styrenes, 1,2-disubstituted allyl alcohols, a-
substitutedacrylamides,1,3-disubstitutedhomoallylalcohols,andY,5-unsaturatedketones.
AnewexampleofaGrovenstein-Zimmermanrearrangementisobservedasasecondary
processduringthesynthesisofenones.
Ageneralregiospecificmethodforthesynthesisof/7-nitroaryl-diarylmethaneshas
beendevelopedstartingfromdiarylmethanolsand2-and/or3-substitutednitrobenzenes.
Thisutilizesthequantitativecondensationbetweenbenzotriazoleanddiarylmethanolsunder
acidic catalysis and in the presence ofperfluorocarbon fluids, followed by vicarious
nucleophilicsubstitutionoftheresultingdiarylmethylbenzotriazolesuponnitrobenzenesin
moderatetohighyield.These vicarious nucleophilic substitutions complement Friedel-
Craftsreactionsforthesynthesisoftriarylmethanes.Oxidativenucleophilicsubstitutionof
hydrogen,whichisobservedasasideprocessduringvicariousnucleophilicsubstitution,
isutilizedforthesynthesisof4-nitrobenzophenones.
vii
CHAPTER
GENERALINTROD1UCTION
Theimportanceofcarbon-carbonbondformationinorganicchemistrycannotbe
overemphasized.Whilefunctionalgrouptransformationsgiveanorganicmoleculeitscast,
carbon-carbonbondformingprovidesthebackbone.Byutilizingthesetwomajor"batde
fields",organicchemistscanmeetthegrowingneedformoleculesthatareabletofitintoa
givenmolecularenvironmentandbindefficientlytospecificreceptors(forrecentreviews
onmolecularrecognitionsee[96AG(E)2589,97CBR23]).
Benzotriazoleisaneffectivesynthetic auxiliary.Itischeapandreadily recycled
whilemostofitsderivativesarestableandeasytoprepare.Thetwo characteristics of
benzotriazolethatmakeitanexcellentcarbon-carbonbondforming agentareitsleaving
groupabilityanditsbehavioras activator towards proton loss [95S1315]. This work
shows how these two features can be interwoven to accomplish the ultimate goal of
carbon-carbonbondformation.
products
1.1 1.2 1.3
Figure1.1
Thegeneralapproachdescribed inthisworkisbestshown in Figure 1.1. The
hydrogenatomin1.1canbeeasilyabstractedtoafford1.2 becauseofthearomaticityof
thebenzotriazolering,andtheexistenceofelectron-attractingpyridine-likenitrogenatoms
[95S1315].ThisprocessisregiospecificandoccursonlywheneitherXorRorbothare
activatinggroups. Throughoutthisworkthea-positionin 1.1 isactivatedbyonearyl
1
2
group(Chapter2,4and5),bytwoarylgroups(Chapter5)orbythetrimethylsilylgroup
(Chapter3).
The carbanion 1.2 can be trapped by electrophiles (E) to afford the "a-
benzotriazolylalkylation"product1.3. Aldehydes,ketones, acidchlorides, isocyanates,
enones,oxiranes,alkylhalidesandelectron-deficientarenesallreactcleanlyandefficiently
with1.2attemperaturesrangingfrom-78"C(Chapters2,3,and4)to-20"C(Chapter5)
toaffordadducts 1.3 thusprovingthegeneralityofthisreaction.The nature ofthese
reactions allow for "one-pot" procedures, wherein the adduct 1.3 can be further
transformedintoproductswithoutisolation(Chapter2).
Theehminationofbenzotriazolefrom 1.3 isthekeystepofthis methodology.
New,milderandmoreefficientmethodsforbenzotriazoleeliminationcomprisethescope
ofthiswork. Oneofthemostfrequentlyused reagent for benzotriazoleelimination is
ZnBr2.WhenEisanaldehydeoraketone(Figure1.1),theresultingalkoxideunderwenta
pinacol-typerearrangementduringwhichdepartureofthecomplexed benzotriazole was
assistedbythemigrationofanadjacentcarbonatomtoaffordthecarbon-insertionproduct
(Chapter2).WhenR=SiMe,whileX=OMe,thereactionof1.2 withaldehydesor
ketonesunderwenttheexpectedPetersonolefinationtoaffordtheenoletherswhichwere
hydrolyzedwithZnBrjandacidtothecorrespondingone-carbonhomologatedcarboxylic
acids(Chapter3). Anewmethodofbenzotriazoleremovalwasrevealedwhen 1.2 was
reactedwithnitro-arenesinpresenceofexcessbase. Thea"adductsthatareformedas
intermediates underwent base promoted elimination of benzotriazole to give C-linked
functionalizednitroarenes(Chapter5).Thesubstrates1.1 whereX-CH^SiMe,andR=
aryl react following the approach shown in Figure 1.1, while the elimination of
benzotriazoleisaccomplishedbyvicinaleliminationofsiliconbyoneofthreeprocesses
depending upon the structure of the electrophile: pyrolysis, [1,4] C->0 Brook
rearrangement, or fluoride induced P-elimination to afford the corresponding terminal
alkenes.
3
In summary, astudy ofa variety of C-C bond forming reactions has been
undertakenwithbenzotriazoleasasyntheticauxiliary.Thesereactionsincluderegiospecitic
insertionofanaryl-andheteroaryl-bearingcarbon,homologationofaldehydesandketones
tothecorrespondingcarboxylicacids,nucleophilicsubstitutionofhydrogeninnitroarenes
withcarbonnucleophiles,anda-aryl-alkenylationofavarietyofaldehydes,oxiranes,alkyl
halides,isocyanatesandacylchlorides.