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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.

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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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