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University of Groningen
Carbon-carbon bond formations using organolithium reagentsHeijnen, Dorus
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Chapter 1: Introduction
Organolithium Reagents : Discovery, Preparation, Properties and
Applications
Wilhelm Schlenk, the discoverer of alkyllithium reagents.
1.1 Discovery and preparation “Methyllithium ignites in air and burns with a luminous red flame and a golden-colored shower of
sparks”.1 The special properties of organolithium reagents, with its highly reactive ionic character,
were first discovered by Wilhelm Schlenk and Johanna Holz in 1917 by the preparation of methyl-,
ethyl- and phenyllithium.1 Starting from the organomercury compounds, metallic lithium provided
the pyrophoric compounds that are now common reagents in synthetic laboratories and industry.
We are currently 100 years after the discovery of organolithium compounds (and 200 years after the
discovery of metallic lithium), and it has changed our world. The global hunger for lithium anno 2018
might be dominated by the demand for lithium-based batteries, but lithium is also used for the
preparation of the organometallic reagents, which are vital to the field of organic synthesis, and
therefore also for the pharmaceutical and chemical industry.2 Fortunately, the highly toxic
organomercury precursor used by Schlenk in his seminal work is no longer used in the synthesis,
since the direct reaction with a carbon-halide bond by means of an umpolung reaction proved to be
a much safer substitute.3 The improved synthesis, and use of these organolithium reagents was
developed by some of the giants in organic chemistry. Ziegler, Wittig and Gillman were responsible
for the first major steps in the maturing of organolithium chemistry by properly handling and using
the reagents for reactions such as polymerization, lithium halogen exchange and other metalations.4
It is not only the high reactivity that makes organolithium reagents so popular amongst chemists; the
price of n-butyllithium in combination with its solubility in simple alkanes or aromatic solvents
(pentane/toluene) make it cheap and easy to handle.8 The relatively nontoxic byproduct from any
deprotonation usually consists of butane, and lithium salts which are easily washed away and even
have their own medical application. The preparation of (non commercial) organolithium reagents
from the corresponding halides is usually straightforward by means of reductive lithiation, or lithium
halogen exchange (Scheme 1.1).4
Scheme 1.1 Common organolithium forming reactions
The mechanism of the important lithium halogen exchange is substrate dependent (alkyl vs aryl and
iodide vs bromide).5b Studies on the reaction pathway and structures involved by means of
spectroscopy, competition experiments, isotope labelling and crystallography have been conducted
over the years, and have led to the confirmation of both radical, as well as ate-complex
intermediates (Scheme 2).5c The preparation of aryllithium reagents from the corresponding
arylhalide and an alkyllithium proceeds via nucleophilic attack on the halide, and is hypothesized to
yield the aryllithium reagent in a concerted fashion, or via a relatively stable ate-complex
intermediate, which collapses to give the most stable product.5c For alkyl bromide substrates, it is a
single electron transfer between the alkyl bromide and the organolithium reagent that yields an
alkyl-radical species, which after a second electron donation results in the anionic alkyl fragment. For
alkyl iodides however, this mechanism has not been proven, since products arising from radical
formation and consecutive cyclization were not detected (Scheme 1.2).5d
Scheme 1.2 lithium-halogen exchange, mechanism and intermediates
Beside the standard safety precautions with respect to toxicity or corrosiveness, working with
organometallic reagents, and alkyl-lithiums in particular, requires proper training and safe handling
to prevent unwanted exposure to air/water that can cause the spontaneous ignition.5e Though
serious (lethal) accidents have happened,10 organolithium reagents are used throughout the world
and can be safely applied on a small as well as a large scale.
1.2 Properties Already in an early stage, the pioneers in the field found that organolithium reagents existed not as
monomers in solution, but provided stable aggregates (Figure 1.1), the size of which varies with alkyl
substituent, solvent and additive.5f The alkyllithium reagents react differently with additives and
solvents, and the rate thereof is often described as the time required to reduce the initial
concentration by half (½ life). In Table 1.1 some of the aggregation states and other properties of the
most common organolithium reagents are shown.5a
Table 1.1. Common (commercially available) organolithium reagents and their properties
R-Li PhLi (Bu2O) MeLi (Ether) n-BuLi (Hex) iPr-Li (Cyclohex) t-BuLi (Pentane)
pKa 43 48 50 51 53
Aggregation
state
Dimer Tetramer Hexamer Tetramer Tetramer
½ life in THF >100 h >100 h 2 h 1 min ½ min
Figure 1.1 Aggregation states or organolithium reagents
The aggregation state of the reagent is of great importance for its reactivity, and can quite easily be
influenced by solvents or additives.5a (This will also show to be a key aspect in the cross coupling
reactions presented in later chapters.) Some of the common solvents and additives are shown below
(Figure 1.2). The coordinating effect of the lone pairs in the heteroatom of ethers or (tertiary) amines
shifts the aggregate toward the monomer or dimer and by doing so, a more reactive species is
formed. In contrast to Schlosser (KOtBu + RLi) type reaction mixtures, the mentioned additives
change the reactivity of the organolithium without altering the chemical nature or pKa of the
organolithium reagent.5g
Figure 1.2 Common solvents and additives for organolithium reagents
The high basicity of the carbanion makes (alkyl) organolithium reagents a common choice when it
comes to strong bases. Illustrative examples of deprotonations are shown below in Figure 1.3.
Lithium Diisopropyl Amide (LDA) and its silyl- analogue lithium hexamethyldisilamide (LiHMDS) are
made by deprotonation of the corresponding amine, which generates the non-nucleophilic bases
that are widely used for a range of (alpha-) deprotonations to form kinetic enolates. Furan is readily
deprotonated, and for consecutive cross coupling, is generally used via a transmetallation step with
boron, zinc or tin reagents.6b Alkyl substituted fluorene molecules are useful building blocks for the
emerging field of organic materials, and the corresponding alkyl chain can easily be installed by a
substitution reaction with the lithiated fluorene.6c Ortho lithiation of substituted benzenes has been
pioneered by (amongst others) Snieckus and Beak, and has paved the way for an easy, fast and high
yielding method for installing ortho-subsitutents on arenes.6d Finally, THF is one of the solvents that
can have a strong effect on the aggregation state of the organolithium reagent, but as a solvent is
also prone to react as proton donor, and after lithiation undergo a ring opening (retro 3+2 ring
closing) to yield the enolate of acetaldehyde as well as ethylene.5
Figure 1.3 Examples of lithiations by alkyllithium reagents
Historically, one of the first reactions where the organolithium reagent showed nucleophilic behavior
was found during its very synthesis, where it reacted with the starting material halide in the Wurtz
type coupling.6a As commonly seen for (strong) bases, organolithium reagents also generally possess
a strong nucleophilic character. At room temperature, they easily react with any carbonyl moiety,
epoxide or nitrile.5 Be it desirable or an unwanted side reaction, these additions are generally very
fast, and as such often outcompete other reaction pathways. As the solvent has a great effect on the
aggregation state and thus the reactivity of the organolithium reagent, it also controls the selectivity
between (for example) transmetallation and addition to an electrophile or lithium halogen exchange.
Figure 1.4 Examples of reactivity of n-butyl-lithium
Figure 1.4 shows some examples of interactions of butyllithium with electrophiles. Lithium halogen
exchange, deprotonation and ortho-lithiation were already mentioned. Together with the elimination
of (for example) alkyl halides, these transformations do not incorporate the alkyl fragment of the
organolithium reagent. In contrary to this, the addition of butyllithium to benzaldehyde yields the
corresponding 1,1-phenyl-butylmethanol. The rate and selectivity for this reaction is difficult to
compete with, and the addition of benzaldehyde can therefore be used to capture excess
organolithium reagent and thereby determine yields/conversions.7a The (carbo)lithiation of styrene
was one of the first reactions performed by Ziegler, and depending on the order of addition of the
reagents yields the intermediate shown above (figure 1.4), or upon reversed (n-Buli added to
styrene) addition triggers the polymerization of styrene to oligo/poly-styrene.1 Methyl iodide will
rapidly react with many nucleophiles, and organolithium reagents are no exception to this, explaining
why it is one of the most used trapping agents. Though ethyl- and other alkyl iodides also undergo
substitution, they are also susceptible to elimination and thereby generate the corresponding
alkene.8 Finally, the trapping of organolithium reagents with carbon dioxide yields the corresponding
lithium carboxylate that upon protonation gives carboxylic acids
1.3 Transmetallations and catalysis Stoichiometric transmetallation of organolithium reagents to zinc, tin or boron has found widespread
use in the preparation of (air) stable organometallic reagents which provide suitable coupling
partners for transition metal catalysis.6b The lowering of reactivity of the organolithium (or
organomagnesium) reagent is balanced by means of a gain in stability, reaction control and
functional group tolerance.6b A clear preference in favor of the softer organometallic reagents has
led to numerous transmetallation strategies and has left the direct use of organolithium reagents an
underexplored area.7b However, additional transmetallations increase the waste production, toxicity
and cost of a reaction, and are therefore inherently less (atom) efficient. The transmetallations to
these other metals, and their use in transition metal catalysis (cross-coupling, palladium used as
example) are shown in Scheme 1.3. It is this catalytic cycle that is believed to take place in in
reactions such as Kumada, Stille, Negischi, Suzuki and Hyiama cross coupling methods, and consists
of an oxidative addition into the carbon-halide bond of the electrophile, followed by transmetallation
with the organometallic reagent of choice. Finally, reductive elimination yields the desired cross
coupling product, and regenerates the active palladium catalyst. In the case of palladium(II)
precatalysts, this cycle is preceded by activation by means of reduction. This can be achieved by
double transmetallatoin with the organometallic coupling partner followed by reductive elimination.
As a consequence, this yields a catalytic amount of homo-coupled byproduct.
Scheme 1.3 Transmetallations using organolithium reagents, and their use in transition metal catalysis
Beside the above mentioned transmetallations with zinc, tin and boron, copper has also found its use
in transmetallation reactions with organolithium reagents.7c, 7d In contrast to the hard organolithium
nucleophile, the formed organocuprate reagent shows properties of a soft nucleophile, and
therefore showcases a remarkable preference for 1,4-addition at the expense of 1,2-addition to the
carbonyl in a 1,4-unsaturated system (Scheme 1.4).8b Whereas organocuprate formation and its use
have been known for decades, the catalytic use of copper with alkyllithium reagents for allylic
substitution reactions was discovered only recently (Scheme 1.4).8c Over the years, the method of
substituting an allylic halide has been found to proceed with both alkyl- and aryllithium reagents, and
for the synthesis of tertiary as well as the very challenging quaternary stereocentres.8c The selectivity
for Sn2’ over Sn2 (Branched : Linear ) product is highly dependent on the solvent, and is easily
controlled by the addition or exclusion of ethereal solvents.
Scheme 1.4 Transformations using organocuprate and organolithium reagents
Direct cross coupling with organolithium compounds
In 1979 Murahashi showed the potential of direct organolithium cross coupling reactions in the
transformation of a range or alkenyl (mostly styryl) bromides (Scheme 1.5).11 For the following
decades, despite being well established reagents by then, organolithiums were exclusively used for
reactions other than (direct) cross coupling reactions. In 2010, Yoshida presented the application of
organolithium reagents in cross coupling reactions by means of flow chemistry, with the in situ
formation of aryllithium reagents.12 Up to this point, both methods were limited in scope (only styryl
or phenyl coupling), but the stage was set for further development.
Scheme 1.5 Examples of early organolithium cross coupling chemistry
In 2013 our group published a more general approach for the coupling of organolithium reagents,
employing bulky palladium phosphine complexes.13 It was found that the controlled addition of the
nucleophile as well as a non-coordinating solvent such as toluene was crucial to achieve the desired
results, which suppresses unwanted side reactions or catalyst deactivation. The work describes the
coupling of alkyl, as well as aryl and alkenyl lithium reagents with aryl and alkenyl bromides (Figure
1.5), and although some limits towards functional group tolerance were met, the inherently less
waste producing reagents showed the potential for organolithium reagents to provide a cheap and
environmental friendly substitute for more commonly used cross coupling reactions such as Suzuki,
Negishi or Stille procedures.14 Key findings were the slow addition of the organolithium coupling
partner, and the absence of ethereal solvents such as THF or diethylether (avoiding the de-
aggregation of the organolithium reagent). Toluene showed to be the solvent of choice, and allowed
for rapid (1 h) coupling at room temperature. Expanding the scope, the system was quickly found to
be suitable for a range of hindered substrates by using NHC-ligands,14b yielding tri- or tetra ortho
substituted biaryl motifs that are a common feature in natural products and biologically active
compounds.14c Different strategies for the synthesis of these products are available, but many
require long reaction times with considerable heating, leaving space for improvement.15 Whereas
phosphine ligated palladium complexes had already proven themselves to be the catalyst of choice
for the selective coupling of unhindered alkyl substrates, the sterically congested biaryl products
required a different approach. Very hindered/bulky Pd-carbene complexes had already shown to
speed up the coupling of other cross coupling reactions by facilitating the otherwise slow reductive
elimination to provide the tri- or tetra- ortho substituted biaryl product.16
Figure 1.5 Charactaristic palladium catalyzed organolithium cross coupling reactions : Catalysts and products
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
2) https://minerals.usgs.gov/
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COMPOUNDS, Volume 23 1959 AMERICAN CHEMICAL SOCIETY, ISBN13: 9780841200241
4) a) H. Gilman, F. W. Moore, O. Baine J. Am. Chem. Soc., 1941, 63 (9), 2479–2482. b) K. Ziegler H.
Colonius, Justus Liebigs Ann. Chem. 1930, 479, 135–149. c) G. Wittig, Ber. Dtsch. Chem. Ges. 1931, 64,
2395–2405. d) H. Gilman, E. A. Zoellner, W. M. Selby J. Am. Chem. Soc. 1932, 54, 1957–1962. e) G.
Wittig U. Pockels H. Dröge, Ber. Dtsch. Chem. Ges. 1938, 71, 1903–1912. f) O. Diels K. Alder Justus
Liebigs Ann. Chem. 1928, 463, 1–97. g) K. Ziegler F. Crössmann H. Kleiner O. Schäfer, Justus Liebigs
Ann. Chem. 1928, 463, 98–227. h) H. Gilman, Jr. Morton, W.John, Org. React. 1954, 8, 258–293
5) a) Lithium Compounds in Organic Synthesis, R. Luisi, V. Capriati, 2014 Wiley‐VCH Verlag GmbH & Co. KGaA ISBN:9783527333431. b) Newcomb, M; Willams, W. G.; Crumpacker, E. L. Tetrahedron Lett. 1985, 26, 1183-1184. Newcomb, M; Willams, W. G. Tetrahedron Lett. 1985, 26, 1179-1182 c) Bailey, W.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1-46. d) E. C. Ashby, Tung N. Pham J. Org. Chem. 1987,52, 1291-1300 e) Michael R. Gau , Michael J. Zdilla, J. Vis. Exp. (117), e54705, doi:10.3791/54705 (2016). f) The Chemistry of Organolithium Compounds, Z. Rappoport, I. Marek, 2004, John Wiley & Sons (Verlag), ISBN: 978-0-470-02110-1. g) M. Schlosser, Pure&Appl. Chem, Vol. 60, 1627-1634, 1988. 6) a) G. M. Lampman, J. C. Aumiller, Org. Synth. 1971, 51, 55. A. Wurtz, Ann. Ch. Phys. 1855 (3), 364
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Coupling Reactions, F. Diederich, P. J. Stang, Wiley‐VCH Verlag GmbH, Online ISBN: 9783527612222
|DOI:10.1002/9783527612222. c) E. Bundgaard, F. C. Krebs, Solar Energy Materials & Solar Cells 91
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