Stereoselective Heterocycle Synthesis via Alkene Difunctionalization

392 Pages·2018·35.45 MB·English

by  David A. Petrone

Springer Theses
Recognizing Outstanding Ph.D. Research
David A. Petrone

Stereoselective
Heterocycle
Synthesis via Alkene
Difunctionalization
Bulky Phosphine Ligands
Enable Pd-Catalyzed
Arylhalogenation,
Arylcyanation and Diarylation
Springer Theses
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David A. Petrone
Stereoselective Heterocycle
Synthesis via Alkene
Difunctionalization
Bulky Phosphine Ligands Enable
Pd-Catalyzed Arylhalogenation,
Arylcyanation and Diarylation
Doctoral Thesis accepted by
the University of Toronto, Canada
123
Author Supervisor
Dr. DavidA.Petrone Prof. Mark Lautens
Laboratory for OrganicChemistry Department ofChemistry
ETHZürich University of Toronto
Zürich Toronto
Switzerland Canada
ISSN 2190-5053 ISSN 2190-5061 (electronic)
SpringerTheses
ISBN978-3-319-77506-7 ISBN978-3-319-77507-4 (eBook)
https://doi.org/10.1007/978-3-319-77507-4
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’
Supervisor s Foreword
The synthesis of medicinally interesting molecules and novel materials has been
dramatically impacted by the discovery of catalytic methods to make carbon–
carbon and carbon–heteroatom bonds. The vast majority of these reactions follow
closely related mechanistic pathways. By far, the most common and fundamental
processes involve oxidative addition and reductive elimination as key steps in the
catalyticcycle.Thesetworeactionsarecharacterizedbyachangeinoxidationstate
of the metal and the cleavage (oxidative addition) or formation (reductive elimi-
nation) of a bond of interest.
The most common process, as it concerns carbon–halogen (C–X) bonds, is
oxidative addition, which is then followed by reaction of the metal–halogen bond
and subsequent reductive elimination to form a C–C or C–Y bond. The inverse
reaction, namely reductive elimination to form a C–X bond, is far less thoroughly
studied and is generally not the favored pathway. Early work by Hartwig and
Milstein focused on stoichiometric reactions and uncovered key requirements for
successfulC–Xreductivebondformation.Inparticular,stericallybulkyligandsand
substrates were found to be essential to form C–Br bonds.
In 2010 and 2011, Stephan Newman from our group demonstrated catalytic
reversibleoxidative additionasakeystepintheformationofCsp2–BrandCsp3–I
bonds using palladium catalysts coordinated to bulky ligands such as tBu P. In
3
addition,NewmandiscoveredthataC–CandC–Ibondcouldbeformedandcalled
thisreactionacarboiodination.HisworksetthestageforthethesisworkofDavid
Petrone.
Chapter1ofthethesisinvestigatedthediasteroselectivityincarbohalogentation
reactions to make novel heterocyclic products. Among the scaffolds prepared by
this methodology were isochromans, chromans, and dihydroisoquinolines. Petrone
then usedthe carboiodination reactionintheformal synthesis ofa natural product.
Histargetwasanalkaloidknownas(+)-corynolineandhewasabletoprepareitin
enantiomericallyanddiasteromericallyenrichedformusingaryliodinationasakey
step.
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vi Supervisor’sForeword
Chapter 2 set out to address a particular challenge arising from the synthesis
describedabove,namely,thedisplacementofaneopentylC–Ibondbycyanide.An
alternative strategy was developed involving a carbocyanation rather than a car-
boiodination. An improved yield and efficiency of the synthesis was achieved by
adding cyanide as a nucleophile to the reaction. With the goal of carbocyanation
achieved,PetroneextendedhisstudytoadditionofC–CNacrossaromaticsystems
such as indoles, resulting in a dearomative carbocyanation. Dearomatic processes
have become of increasing interest, but less was known about difunctionalization
of the C=C of the indole. A particular challenge was the easy epimerization at the
benzyliccyanidethatresultsfromthecarbocyanation.Fortunately,carefulchoiceof
solvent and catalyst overcame this hurdle.
Chapter 3 set out to generalize the carbofunctionalization of the indole, and a
1,2-arylation was achieved by combining carbopalladation with a Suzuki-type
couplingtoformadiarylationoftheindolealkene.Arylboroxinesprovedtobethe
idealnucleophilessothatcarbopalladationofthealkeneproceedsfasterthandirect
Suzuki coupling.
Chapter4highlightsaparticularlyimportantfindingwhenconsideringreversible
oxidative addition of C–I bonds. Petrone prepared substrates with two aryl C–I
bonds and, through a careful synthetic and mechanistic study, showed that each
undergoes insertion by bulky Pd(0) complexes at a similar rate. By linking an
acceptor in proximity to one of the aryl C–I bonds, it was possible to do a car-
boiodination while leaving the other aryl C–I bond “untouched.” Of course that
bond had also undergone reaction, but in a reversible fashion. In fact by adding a
second acceptor (external), both C–I bonds could be orthogonally reacted. One
underwentcarboiodination,andtheotheraHeckreaction.Thisstudydemonstrated
the power of reversible oxidative addition in polyhalogenation compounds.
Overall Petrone thesis built on a recent finding in the group and took the
chemistry into completely new and unexpected ways. The potential of carbofunc-
tionalization was revealed through synthetic and mechanistic work, and the reac-
tions he discovered were applied to target molecules with biological activity.
Toronto, Canada Mark Lautens
February 2018
Preface
My Ph.D. studies in the research group of Prof. Mark Lautens at the University of
Torontofocusedonusingpalladiumcatalystsmodifiedbybulkyphosphineligands
to promote the highly stereoselective formation of several classes of heterocycles.
My initial venture into this research topic was initiated during study aimed to
examine the stereoselective synthesis of chromans and isochromans via the
cyclizationstrategywhichhasbeendesignated“arylohalogenation”throughoutthis
thesis. This project was initiated by a talented post-doctoral fellow named
Dr. Hasnain Malik who mentored me during my studies. The knowledge gained
throughoutthisprojectledtoourgroup’smoregeneralinterestinthestereoselective
syntheses of other classesof halogenated heterocycles.
From here, in collaboration with Hyung Yoon and Dr. Harald Weinstabl, a
highly scalable and asymmetric route to dihydroisoquinolinone scaffolds was
developedusingthearyliodinationmethodology.Thisreactionwas laterutilizedin
key step in our synthesis of the bioactive alkaloid natural product (+)-corynoline.
The difficulties associated with a particular cyanation step within our validated
synthetic route led to the development of an efficient and highly stereoselective
arylcyanationreactionasasolution,whichminimizedtheuseofcostlyligandsand
excessamountsoftoxiccyanatingreagents.Sincethearylcyanationreactionforms
two carbon‒carbon bonds, all while incorporating a useful nitrile functional group
handle, we aimed to expand the scope of this transformation to the preparation of
fused indolines. With the assistance of Andy Yen and Nicolas Zeidan, an efficient
and highly stereoselective preparation of fused indolines was accomplished using
simple indole substrates in a dearomative process. This efficient dearomative
difunctionalization concept was expanded to the stereoselective indole diarylation
in a joint effort between myself and a visiting Japanese scholar named Dr. Masaru
Kondo.
Substrates that are functionalized with a carbon–halogen bond allow for a high
degreeofregiocontrolincross-couplingreactionssincethemetalcatalysthasahigh
propensity to activate the molecule via oxidative addition at this site. However,
because of the potential for over-coupling, non-site elective coupling, and catalyst
deactivation,syntheticplanningcanbecomechallengingwhenamoleculecontains
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viii Preface
multiplecarbon–halogenbonds.AvisitingGermanstudentMatthiasLischkaandI
developed a protocol to utilize diiodinated aromatic compounds in both a
site-selective Pd-catalyzed intramolecular aryliodination and an intramolecular
aryliodination/intermolecular Mizoroki-Heck reaction. These two processes relied
on the unique ability of the judiciously chosen palladium catalyst to undergo
reversible oxidative addition to aromatic carbon–halogen bonds, and this rare
characteristic is what allows this reaction to proceed to high levels of conversion.
In general, this thesis brings to light the true power of sterically hindering
ligands beyond their commonplace in challenging cross-couplings. Their unique
characteristics have opened up several new avenues regarding carbon–carbon and
carbon‒halogen bond formation, and are surely to have continued and expanding
impact on many fields which rely on catalysis to prepare molecules via the for-
mation of bonds that would otherwise be difficult.
Zürich, Switzerland David A. Petrone
January 2018
Parts of this thesis have been published in the following journal articles:
1. “Modern Transition Metal-Catalyzed Carbon−Halogen Bond Formation,”
Petrone, D.A.; Ye, J.; Lautens, M. Chem. Rev. 2016, 116, 8003–8104.
2.“Pd-CatalyzedDearomativeDiarylationofIndoles,”Petrone,D.A.;Kondo,M.;
Zeidan, N.; Lautens, M. Chem. Eur. J. 2016, 22, 5684.
3. “Dearomative Indole Bisfunctionalization via a Diastereoselective
Palladium-Catalyzed Arylcyanation,” Petrone, D.A.; Yen, A.; Zeidan, N.;
Lautens, M. Org. Lett. 2015, 17, 4838–4841.
4.“Pd-CatalyzedCarboiodination:EarlyDevelopmentstoRecentAdvancements,”
Petrone, D.A.*, Le, C.M.*; Newman, S.G.; Lautens, M., in New Trends in
Cross-Coupling: Theory and Application, T. Colacot, Ed.; The Royal Society of
Chemistry: Cambridge, 2015, chapter 7. *Equal contribution.
5. “Synergistic Steric Effects in the Pd-Catalyzed Alkyne Carbohalogenation:
Synthesis of Tetrasubstituted Vinyl Halides,” Le, C.M.; Menzies, P.; Petrone, D.
A.; Lautens, M.: Angew. Chem. Int. Ed. 2015, 54, 254–257.
6. “Diastereoselective Palladium-Catalyzed Arylcyanation/Heteroarylcyanation of
Enantioenriched N-Allyl Carboxamides,” Yoon, H.*; Petrone, D.A.*; Lautens,
M.: Org. Lett. 2014, 16, 6420–6423. *Equal contribution.
7. “Additive Effects in the Pd-Catalyzed Carboiodination of Chiral N-Allyl
Carboxamides,” Petrone, D.A.; Yoon, H.; Weinstabl, H.; Lautens, M.: Angew.
Chem. Int. Ed. 2014, 53, 7908–7912.
8. “Harnessing Reversible Oxidative Addition: Application of Diiodinated
Aromatic Compounds in the Carboiodination Process,” Petrone, D.A.; Lischka,
M.; Lautens, M.: Angew. Chem. Int. Ed. 2013, 52, 10635–10638.
9. “Functionalized Chromans and Isochromans via a Diastereoselective
Pd-Catalyzed Carboiodination.” Petrone, D.A.; Malik, H.A.; Clemenceau, A.;
Lautens, M.: Org. Lett. 2012, 14, 4806–4809.
10. “A Conjunctive Carboiodination: Indenes by a Double Carbopalladation–
Reductive Elimination Domino Process.” Jia, X.; Petrone, D.A.; Lautens, M.:
Angew. Chem. Int. Ed. 2012, 51, 9870–9872.
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