University of Groningen Carbon-carbon bond formations using organolithium reagents Heijnen, Dorus IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2018 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Heijnen, D. (2018). Carbon-carbon bond formations using organolithium reagents. University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 01-12-2021
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University of Groningen
Carbon-carbon bond formations using organolithium reagentsHeijnen, Dorus
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.
Document VersionPublisher's PDF, also known as Version of record
Publication date:2018
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):Heijnen, D. (2018). Carbon-carbon bond formations using organolithium reagents. University of Groningen.
CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.
Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.
The Pd-PEPPSI complex shown in Figure 1.5 was found capable of catalyzing these reactions with
remarkable selectivity and conversion for a reaction that is carried out in just one hour at room
temperature.14d As electrophile, aryl bromides and the cheaper and more stable aryl chlorides were
both found to be active, and the method was showcased in the facile synthesis of sterically
demanding BINOL-derived products.17 The amount of solvent had surprisingly little effect, and these
hindered biaryls were later also synthesized in the absence of any additional solvent (vide supra),
creating a general, low solvent method for the synthesis of these motifs (Scheme 1.6).14e This
resulted in an improved synthesis of key intermediates, including 4-chlorophenyl-thiophene, with
significant lower E-factors and reduced reaction times.
Scheme 1.6 Solvent free cross coupling of organolithium reagents
Faster
A positive effect in terms of reaction speed was observed when the once thought to be crucial
solvent toluene was completely omitted, and the reaction was carried out using the substrate as the
solvent for the palladium NHC catalyst.14e Solvents are often deemed crucial for reactions and cross
coupling chemistry in particular, and little is known about extremely concentrated reaction
mixtures.18 We observed that under these high concentrations, products were now obtained in 10
min at room temperature and the strict inert conditions were no longer required (vide supra). The
impact of omitting the additional solvent in these reactions greatly enhances the waste to product
ratio described by the E-factor and at the same time increases the effective capacity of the
(laboratory) setup.19 Having only a catalytic amount (down to 1.5 mol%) of Pd-complex, and benign
lithium salts as the only stoichiometric waste, the method yielded very clean reaction mixtures, that
after a quick filtration step were obtained analytically pure. Simultaneously, in order to test the limits
of the palladium phosphine complex that were previously employed in the general cross coupling
procedure, the addition time of the solution of alkyl (methyl) lithium was graduately decreased. With
addition times of just 2 min, full conversion with near perfect selectivity was still achieved (Scheme
1.7).20
Scheme 1.7 Oxygen activated fast cross coupling
The initial notice of methyl lithium being a special case was quickly found to be incorrect when other
alkyllithium reagents gave identical results. Testing different batches of the commercially available
Pd(PtBu3)2 complex, results began to vary greatly. A systematic approach, ruling out a large variety of
factors finally showed molecular oxygen to be essential for the fast coupling. Further studies showed
that purging with molecular oxygen yielded an extremely active catalyst, that consisted of palladium
nanoparticles.20b After full activation of the catalyst, manual addition of alkyllithium over a period of
5 sec gave full conversion of the starting material, with good selectivity towards the desired product
(Figure 1.6).
Figure 1.6 Optimization of catalytic systems
All mentioned catalytic setups show great selectivity for cross coupling at the expense of (for
example) lithium halogen exchange. But what if lithium halogen exchange at the expense of cross
coupling is desired? Ethereal solvents such as THF are well known to change the aggregation state of
the organolithium reagent enhancing their reactivity, but also therefore hamper the desired direct
cross coupling reaction.21 Whereas n-BuLi and sec-BuLi couple with excellent yields, the most reactive
of the butyl series, t-BuLi does not participate in the catalytic cycle. Since transmetallation of the
tertiary alkyllithium with the palladium catalyst is not favored, lithium halogen exchange with an aryl
halide is next in the line of events, and will create the corresponding aryllithium coupling partner in
situ (Scheme 1.8).
Scheme 1.8 tBuli mediated In situ formation and coupling of aryllithium reagents
The palladium catalyzed coupling of this in situ made aryllithium with the remaining excess aryl
halide presented little challenge in the case of symmetrical biaryls.22 For a highly selective
heterocoupling however, an ortho directing group facilitates significant faster lithium-halogen
exchange in one of the substrates (Pathway B), and slows down oxidative addition with the palladium
(0) catalyst, thereby creating a selective process of forming a single aryllithium reagent. With the
selective in situ preparation of the organometallic reagent, the remaining (less reactive towards
lithium-halogen exchange) aryl bromide solely reacts with the palladium(0) catalyst via oxidative
addition (Pathway A), generating the palladium(II) intermediate that undergoes transmetallation
(TM), followed by reductive elimination (RE) to yield the desired cross coupled product.23
Cheaper
Compared to other more established cross coupling methods, the intrinsically cheaper and more
environmentally benign organolithium reagents provide a perfect platform for an exceedingly cost
efficient cross coupling.23b As has been done for other cross coupling methods, we envisioned we
could avoid the use of bromide electrophiles and palladium catalysts, and employ aryl chlorides and
nickel complexes instead. Cheaper transition metal catalysts such as nickel were already investigated
by Rueping and Chatani (amongst others) in for example the cross coupling of the bifunctional Li-
CH2TMS with aryl ethers and have previously shown to be active in Kumada, Suzuki and Negishi
coupling reactions.24 For the lithium chemistry, a clear similarity between nickel and palladium
catalysis was observed after careful optimization of the catalytic system.25 An alkylphosphine based
nickel catalyst proved to be the most suitable candidate for the coupling of alkyllithium reagents,
whereas (hindered) aryllithium reagents proved most compatible with a carbene-nickel complex
(Scheme 1.9).
Scheme 1.9 Palladium vs Nickel catalysis
The much less reactive methoxide and fluoride electrophiles, could also be activated, allowing for the
late stage functionalization of molecules.26 Additional studies on the coupling of organolithium
reagents with not only these often inert ether groups, but also ammonium salts was published the
same year by Wang and Ochiyama.27 In the cross coupling with aryllithium reagents, a near identical
functional group tolerance was observed, leading to substituted biaryl products.
Functional group compatibility
Some substrates and applications deserve special attention due to their applicability or remarkable
selectivity. The previously discussed strong basic and nucleophilic character of organolithium
reagents provide some challenges in their cross coupling. It is therefore surprising to see that our
developed method(s) are capable of selectively incorporating the organolithium reagent, suppressing
nucleophilic attack to a large extend (Figure 1.7A ). One of the key examples of this selectivity, is the
cross coupling wit aryl bromides in the presence of unhindered epoxides, with minimal side products
arising from ring opening reactions. Though further electrophilic sites are absent in indoles and
alcohols, the corresponding alkoxide or amide (generated upon deprotonation) is prone to interfere
with the palladium catalyst. Yet, we were able to use a variety of alcohols (including phenol),
unprotected indole, as well as sulfonamides (vide infra) (Figure 1.7B). Finally, the exclusive coupling
with bromides at the expense of triflates or chlorides provides a vital chemoselectivity that leaves
room for additional/further functionalization with the less reactive electrophilic center
(Figure 1.7C).28
Figure 1.7 Special examples of selectivity obtained with the Pd-Phosphine precatalyst.
Similar chemoselectivity with respect to bromides and chlorides to that of the one shown above was
also found in the Pd-PEPPSI catalyzed, temperature controlled, cross coupling with
bromochloroarenes (Scheme 1.10). Lowering reaction temperatures, full selectivity was observed in
the coupling of alkyllithium reagents. Unlike the phosphine based nanoparticle catalyst, the Pd-
PEPPSI catalyst that showed this distinction, is also very active with the less reactive aryl chlorides,
but only at (or close to) room temperature. Moreover, previous work showed the Pd-NHC complex to
be a very suitable catalyst for other cross coupling methodologies such as aminations and Negishi
and Stille coupling reactions.29 This allowed us to develop a method for the temperature controlled,
one pot cross coupling of bromo-chloro-arenes to provide highly functionalized small molecules with
excellent diversity of the desired substituents.30
Scheme 1.10 Examples of functionalized molecules synthesized via a sequential one pot procedure30
Specialized Pd-PEPPSI catalysts were synthesised and tested in the coupling of alkyllithium reagents,
and even proved capable of coupling it to iodonaphthalene at -78°C. This is the first example of
reactivity with these reagents at such low temperatures, and could pave the way to new selectivity
and reactivity that is impossible using conventional cross coupling methodology.30
Applications
The synthesis of natural products has always attracted the attention of organic chemists to prove or
validate the power of their developed methodology.24c The first synthesis of a natural product using
an organolithium cross coupling was shown by the preparation of Mastigophorene A (Figure 1.8). The
previously synthesized dimethyl herbertenediol could easily be brominated and subsequently
homocoupled to give the natural product. The axial chirality in the biaryl was installed with a 9.1 d.r.
Since a non-chiral (Pd-PEPPSI-Ipent) catalyst was used, the point to axial chirality transfer is
hypothesized to be transferred via the large ligand on the palladium catalyst.
Figure 1.8 Applications of organolithium cross coupling.
The above mentioned fast coupling of alkyl lithium reagents also paved the way for the incorporation
of short lived radio isotopes that require short reaction times for high yielding reactions. The
radiolabeling of biologically active compounds allows us to map their distribution throughout the
human body, and elucidate their mode of action via PET imaging.25b The unique rate of the cross
coupling is especially suitable for the synthesis of PET-tracers, since it allows for radiolabeled drugs to
be constructed in shorter times, and thus with a lower extend of decay, generating an overall more
efficient synthesis. Celecoxib is a widely used anti-inflammatory drug, and was chosen as target to
showcase the power of the organolithium cross coupling methodology.25c Not only biologically active
compounds are within the scope of organolithium cross coupling chemistry, as showcased by the
improved synthesis of building blocks for optoelectronic material, and the preparation of highly
sterically congested BINOL derrivatives. These biaryls with axial chirality are crucial precursors in the
synthesis of ligands for transition metal catalysis, as well as chiral phosphoric acids for asymmetric
organocatalysis.25d
To conclude, the cross coupling of organolithium reagents has shown great potential in the
environmentally friendly, fast and cheap construction of carbon-carbon bonds. By means of slow
addition of the nucleophile, and by employing the proper solvent, notorious side reactions can be
suppressed, and the desired products are generally isolated in high yields. Natural products,
pharmaceuticals and (precursors to) optoelectronic materials and ligands are within the scope of the
methodology.
The method that is applicable to the coupling of the bifunctional LiCH2TMS reagent is described in
chapter 2, and has led to the synthesis of TMS-substituted toluene derivatives, suitable for a range of
transformations. The first application of the organolithium based coupling in the synthesis of a
complex natural product, and other (sterically hindered) biaryl structures is presented in chapter 3. In
chapter 4, several one pot procedures are described. Briefly looking back at the previously reported
method for the synthesis of aryl-alkyl ketones, these new approaches provide novel strategies for the
synthesis of an array of α-substituted ketones, substituted benzaldehydes or anilines. The attempts
at utilizing the advantageous properties of the organolithium cross coupling in the atroposelective
construction of chiral biaryls by employing bulky Pd-NHC complexes are described in chapter 5.
Moving away from palladium to more earth abundant metals, nickel was found to be very active in
the cross coupling of both alkyl and aryllithium reagents with a range of aryl bromides and chlorides,
but unlike palladium, also with the less reactive methoxy substituted aryl compounds and
arylfluorides. These results are described in chapter 6. The suprising effect of molecular oxygen in the
activation of palladium phosphine complexes, and their considerable effect in the rate of the reaction
is shown in chapter 7. This chapter also explains the application of the oxygenated catalyst in the
synthesis of radiolabeled pharmaceuticals. Further applications in the synthesis of pharmaceuticals
can be found in chapter 8, where the atom efficient preparation of Z-tamoxifen is achieved by a
carbolithiation-cross-coupling strategy. Finally, the combination of organolithium cross coupling
reactions, that proceed at cryogenic temperatures, with more traditional cross coupling methods
such as Suzuki, Negishi or Buchwald-Hartwig is presented in the final chapter 9.
1.4 References. 1) U. Wietelmann, J. Klett Z. Anorg. Allg. Chem. 2018, 644, 194–204 and references therein
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Colonius, Justus Liebigs Ann. Chem. 1930, 479, 135–149. c) G. Wittig, Ber. Dtsch. Chem. Ges. 1931, 64,
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7) a) This thesis b) Less than 20 papers on the direct cross coupling of organolithium reagents have been published to date. c) N. J. Rijs, N. Yoshikai, E. Nakamura, R.A. J. O’Hair J. Org.Chem. 2014, 79, 1320–1334 d) Organocuprate Aggregation and Reactivity: Decoding the 'Black Box, Aliaksei Putau, Südwestdeutscher Verlag für Hochschulschriften, ISBN-13: 978-3838136981
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