University of Groningen

Direct catalytic cross-coupling of organolithium compoundsGiannerini, Massimo; Fananas Mastral, Martin; Feringa, Ben L.

Published in:Nature Chemistry

DOI:10.1038/NCHEM.1678

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Citation for published version (APA):Giannerini, M., Fananas Mastral, M., & Feringa, B. L. (2013). Direct catalytic cross-coupling oforganolithium compounds. Nature Chemistry, 5(8), 667-672. https://doi.org/10.1038/NCHEM.1678

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Direct catalytic cross-coupling of organolithiumcompoundsMassimo Giannerini, Martın Fananas-Mastral and Ben L. Feringa*

Catalytic carbon–carbon bond formation based on cross-coupling reactions plays a central role in the production of naturalproducts, pharmaceuticals, agrochemicals and organic materials. Coupling reactions of a variety of organometallic reagentsand organic halides have changed the face of modern synthetic chemistry. However, the high reactivity and poor selectivityof common organolithium reagents have largely prohibited their use as a viable partner in direct catalytic cross-coupling.Here we report that in the presence of a Pd-phosphine catalyst, a wide range of alkyl-, aryl- and heteroaryl-lithiumreagents undergo selective cross-coupling with aryl- and alkenyl-bromides. The process proceeds quickly under mildconditions (room temperature) and avoids the notorious lithium halogen exchange and homocoupling. The preparation ofkey alkyl-, aryl- and heterobiaryl intermediates reported here highlights the potential of these cross-coupling reactions formedicinal chemistry and material science.

Transition metal-catalysed cross-coupling reactions for theselective formation of C–C bonds enable the facile preparationof myriad structurally diverse and complex molecules essential

for the development of modern drugs and organic materials1–4.Typically, Pd or Ni catalysis is used with an organic halide, andan organometallic or main-group reagent as nucleophilic couplingpartner1,5, although (directing-group based) coupling via C–H acti-vation has recently emerged as a possible alternative6–8. AlthoughStille (with organotin as the nucleophile)9,10, Suzuki–Miyaura (organo-boron)11,12, Negishi (organozinc)1,13,14, Hiyama–Denmark (organo-silicon)15,16 and Kumada (organomagnesium)17,18 couplings arewell established (Fig. 1a), the direct application of organolithiumreagents (among the most reactive and commonly used reagentsin chemical synthesis19) in cross-coupling reactions remains aformidable challenge. Some of the coupling partners are directlyaccessible; for instance, organoboron compounds can be preparedby hydroboration of unsaturated substrates20 (that is, alkyl andvinyl boranes) or by borylation of C–H bonds21 (alkyl and arylboranes). However, as aryl organoboron and organotin compounds,in particular, are frequently prepared from the correspondinglithium reagents, a concise method, taking advantage of the directuse of organolithium compounds in C–C bond formation, wouldeliminate the need for such additional transformations.Organolithium reagents are cheap and either commercially availableor readily accessible through halogen–metal exchange or directmetallation. Early studies by Murahashi and co-workers22 on theuse of organolithium reagents for cross-coupling reactions revealedthe limitations of this transformation due to the very high reactivityof these organometallic compounds and also the high temperaturesrequired22. One major problem that has precluded the application oforganolithium reagents is the competing formation of homocoupledproducts as a result of fast lithium–halogen exchange precedingPd-catalysed C–C bond formation. Recently, a Murahashi-typebiaryl coupling was performed using a flow-microreactor23, whilein an alternative approach, a stoichiometric silicon-based transferagent was used24. However, the development of an efficient catalyticprotocol for cross-coupling of highly reactive organolithium speciesthat does not suffer from lithium–halogen exchange and homocou-pling has proven elusive until now.

Here, we report a practical method for the fast and highly selec-tive direct cross-coupling of organolithium reagents under mildconditions, and with broad scope, using Pd catalysis. CatalyticC–C bond formation readily proceeds with alkyl-, aryl- and hetero-aryl-lithium reagents, providing a versatile and mild alternative toexisting protocols (Fig. 1b).

Results and discussionsWe anticipated that, to achieve selective cross-coupling of arylbro-mide and organolithium species, fast lithium–bromide exchangehas to be suppressed by efficient transmetallation and the pro-motion of fast oxidative addition and subsequent reductive elimin-ation of the organic moieties by the Pd complex. We hypothesizedthat competing lithium–bromide exchange might be prevented bycontrolling the reactivity and aggregation state of the organolithiumreagent by choosing an appropriate solvent, an approach we recentlytook in catalytic asymmetric allylic alkylations25. The high reactivityof the organolithium species opens the exciting prospect of selectivecross-coupling at room temperature by fine-tuning of thePd-catalyst complex.

R2–Li1 h

Room temperature

R1–Br

Pd catalyst

Selectivity >95%High yieldR1 = alkenyl, aryl, heteroaryl

R2 = alkyl, aryl, heteroaryl

b This work: M = Li

R+

+

2–MR1–X R1–R2

R1–R2

Transition metal catalyst

a Well established methods:

X = halide or sulfonate

Stille (M = Sn); Negishi (M = Zn); Suzuki-Miyaura (M = B); Hiyama-Denmark (M = Si); Kumada (M = Mg).

Figure 1 | Catalytic cross-coupling reactions. a, Established methodology

based on organo-tin, -zinc, -boron, -silicon and -magnesium compounds.

b, Cross-coupling using organolithium compounds.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands. *e-mail: b.l.feringa@rug.nl

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Pd-catalysed cross-coupling with alkyllithium reagents. For ourinitial model reaction (Table 1) we selected 4-methoxy-bromobenzene, a reluctant arylhalide26 in many couplingreactions, and n-BuLi, one of the most reactive organometallicreagents, realizing that successful selective cross-coupling of thesecompounds would mean access to an abundance of othercoupling partners. Using, under an inert atmosphere, 1.2 equiv. ofn-BuLi, XPhos (10 mol%)27 as the ligand in combination withPd2(dba)3 (2.5 mol%, ratio of Pd to ligand of 1:2), toluene as thesolvent to avoid ethereal compounds capable of enhancinghalogen–metal exchange, with dilution (0.45 M) and slowaddition (3 h) of the lithium reagent to avoid excessorganolithium reagent in solution, the reaction led to thepredominant formation of the desired cross-coupling productp-methoxybutylbenzene 2a. Although full conversion is reached atroom temperature, the presence of a small but significant amount(5%) of dehalogenated product 3 (due to Br–Li exchange) andhomocoupled biaryl product 4 (10%), as well as a small amount(5%) of the isomerized cross-coupling product 2x, illustrates themanifold competing pathways (Table 1, entry 1). In a few specificcases, such as the reaction between bromobenzene and n-BuLi intetrahydrofuran (THF)28, the coupling product is obtained in theabsence of a metal complex as a result of halogen–metal exchangeand subsequent alkylation of the aryllithium. However, thereaction with 1a using THF as solvent in the absence of Pdcatalyst gave incomplete conversion, affording a complex mixtureof products (see Supplementary Table S1 for further details).In toluene, the omission of the Pd catalyst resulted in lowconversion and the exclusive formation of dehalogenated product3 (Table 1, entry 2). A dramatic drop in selectivity is observedunder phosphine ligand-free conditions (Table 1, entry 3),implying that the nature of the phosphine ligand is a crucialparameter27,29,30. Screening in situ prepared Pd catalysts withdifferent dialkylbiaryl phosphines29 (Supplementary Table S1) wefound that the use of SPhos enhanced the selectivity towards 2,completely suppressing the isomerization reaction whilesimultaneously shortening the addition time to 1 h (entry 4).However, selectivity higher than 90% could not be achieved usingthis type of ligand (Supplementary Table S1). It should be notedthat the coupling reaction is remarkably fast at room temperatureand is finished upon complete addition of the organolithiumreagent. As hindered trialkylphosphines30 are frequently used in

cross-coupling reactions to enhance reductive elimination andavoiding beta-hydrogen elimination (which is yet anothercompeting pathway to the formation of dehalogenated andisomerized products)31, the ligand P(tBu)3 was also tested. The useof the in situ formed complex from Pd2(dba)3 and P(tBu)3 gaverise to a selectivity comparable with those obtained withdialkylbiaryl phosphines (Table 1, entry 5). When thecommercially available preformed complex Pd[P(tBu)3]2 (5 mol%)was used instead of the in situ formed catalyst, cross-coupledproduct 2a was obtained in high yield and with excellentselectivity, with minimal halogen exchange taking place whilecompletely inhibiting the formation of the homocoupling product4 (Table 1, entry 6). Remarkably, the reaction also proceeds with1 mol% of catalyst, with similar selectivity (Table 1, entry 7).

With the optimal conditions for highly selective alkyl–aryl cross-coupling determined, the scope of the reaction of alkyllithiumreagents and arylbromides was examined (Table 2).

The Pd-catalysed coupling of alkyllithium compounds with aryl-bromides entails substrates bearing halide, alcohol, acetal and etherfunctionalities, electron-withdrawing chlorides and electron-donat-ing methoxy and dimethylamine substituents (Table 2). Withp-chloro-bromobenzene, coupling occurs, as expected, exclusivelyat the bromine-substituted carbon, but with no detectable chloridedisplacement (2c). Polyaromatic compounds such as bromo-naphthalene are regioselectively alkylated at position 1 (2d) or 2(2e–2f ), indicating that benzyne intermediates via 1,2-eliminationare not formed. Remarkably, bromofluorene could be alkylated(2g,2h) using only 1.2 equiv. of the corresponding organolithiumreagent, despite the acidity of the benzylic protons ( pKa¼ 22).The scope of this C(sp3)–C(sp2) cross-coupling also includes alkyl-lithium reagents ranging from the smallest MeLi (2f, 2h) to thosebearing long alkyl chains (2i–2k). The cross-coupling of the functio-nalized lithium reagent trimethylsilylmethyllithium proceeds withexcellent yields (2l–2o). Facile multiple coupling is illustrated withthe twofold alkylation of 4,4′-bis-bromobiphenyl, providing 2p in91% yield. In addition, alkenyl bromides also undergo this cross-coupling with high selectivity, as shown by the coupling between2-bromovinylbenzene and n-BuLi (2q) and (Z)-1-bromopropeneand n-HexLi (2r). It is important to note that the stereochemicalinformation is preserved and no olefin isomerization takes placeduring the reaction. Using this protocol, acetal-protected aldehydeswere also tolerated (2s) without the interference of n-BuLi-mediated

Table 1 | Cross-coupling of n-BuLi and 4-methoxy-bromobenzene.

Br

+

O

nBuLi

O

O

O

O2a 3

4

1a

(1.2 equiv.)O

2x

Toluene, r.t.

Pd complexLigand

Entry Pd complex Ligand Reaction time (h) Conversion (%) 2a:3:4:2x*

1 Pd2(dba)3, 2.5 mol% XPhos, 10 mol% 3 Full 80:5:10:52 – – 3 25 –:.95:–:–3 Pd2(dba)3, 2.5 mol% – 3 22 23:48:29:–4 Pd2(dba)3, 2.5 mol% SPhos, 10 mol% 1 Full 89:5:6:–5 Pd2(dba)3, 2.5 mol% P(t-Bu)3, 6 mol% 1 Full 90:6:4:–6 Pd[P(t-Bu)3]2, 5 mol% – 1 Full 96:4:–:–7 Pd[P(t-Bu)3]2, 1 mol% – 1 Full 95:4:1:–

*Ratio of products determined by gas chromatography analysis.Conditions: 1.2 equiv. n-BuLi (1.6 M solution in hexane diluted with toluene to a final concentration of 0.36 M) was added to a solution of 4-methoxy-bromobenzene (3 mmol) in toluene (2 ml).dba, dibenzylideneacetone; XPhos, 2-dicyclohexylphosphino-2′ ,4′ ,6′-triisopropylbiphenyl; SPhos, 2-dicyclohexylphosphino-2′ ,6′-dimethoxybiphenyl.

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cleavage of the protecting group. Remarkably, substrate 1t, bearingan unprotected hydroxyl group, could also be coupled with thisorganolithium reagent (2 equiv.) to afford alcohol 2t in a goodyield. Although the use of ketone- or nitrile-containing substratesproved to be incompatible with this reaction, mainly due to the for-mation of 1,2-addition side products, compound 1u, bearing anester group, could be coupled with MeLi in moderate yield. Inthis case, it was necessary to use the corresponding aryl iodideand a lower temperature (210 8C) to achieve good selectivity (seeSupplementary Table S3 for details).

A recurring challenge in the field of cross-coupling reactions is toachieve selective C–C bond formation of organometallic reagents

bearing secondary alkyl moieties32,33, without isomerization of thealkyl moiety. The ease of coupling secondary alkyllithium reagentstherefore came as a surprise; both i-PrLi and the more challengings-BuLi undergo Pd-catalysed coupling with arylbromides with elec-tron-donating and -withdrawing substituents in high yields,showing no isomerization at all (2v–2y), presumably due to fasttransmetallation–reductive elimination steps being inherent to thiscatalytic system.

Pd-catalysed cross-coupling with (hetero)aryllithium reagents.With an efficient procedure for aryl–alkyl cross-couplingestablished, we turned our attention to aryl–aryl cross-couplingusing arylbromides and aryllithium reagents (Fig. 2). Although thecoupling of phenyllithium and 4-methoxybromobenzene 1aproceeds in toluene at room temperature using Pd[P(tBu)3]2 ascatalyst, full conversion and selectivity was not achieved. Furtheroptimization of the reaction conditions (Supplementary Table S2)showed that full conversion was restored by using the in situprepared catalyst34 using Pd2(dba)3 and P(tBu)3 as ligand. Bydiluting the PhLi reagent in THF the selectivity was furtherenhanced, but traces of dehalogenated product appeared. Inaccordance with our hypothesis, lowering the amount of THFeliminated this side reaction, and finally using 2.5 mol% Pdcatalyst with a ligand to Pd ratio of 1.5:1 under optimizedconditions resulted in biaryl formation (in 1 h at roomtemperature) with excellent isolated yield and 98% selectivity (Fig. 2).

Studying the scope of biaryl formation via Pd-catalysed cross-coup-ling of a range of arylbromides and aryllithium reagents showed that at20 8C in 1 h the corresponding biaryls 5 are obtained in high yields(Table 3). For example, electron-rich (5a,5b) and electron-poor (5c)phenylbromides and naphthylbromide (5d) were readily arylated. It

Table 2 | Scope of Pd-catalysed cross-coupling of alkyllithium reagents.

RLiToluene, r.t.

Ar–Br +

1

Ar–R

2

Pd[P(tBu)3]2 5 mol%

O

2a, 80%

N

2b, 88%

Cl

2c, 84% 2e, 87%2d, 92% 2f, 83%

2g, 88% 2h, 90%

O

5

O

15

N

5

2i, 88% 2j, 94% 2k, 95%

O

TMS

TMSCl

Cl

TMS

2l, 93%

2n, 93%2m, 97%

ON

O Cl

2v, 75% 2w, 78% 2x, 89% 2y, 79%

2p, 91%

2s, 92%

O

O

2q, 89%

SPh

TMS

2o, 87%

5

2r, 99%*

OH

2t, 61%

CO2Me

2u, 43%†

Conditions: aryl bromide (0.3 mmol), RLi (0.36 mmol, diluted with toluene to reach 0.36 M concentration and added over 1 h), Pd[P(tBu)3]2 5 mol%, toluene (2 ml) at room temperature. Selectivity .95% in allcases, unless otherwise noted.Yield values refer to isolated yields after purification.*GC yield: product was not isolated due to volatility issues.†Reaction carried out with the corresponding aryl iodide, 7.5 mol% Pd[P(tBu)3]2 at 210 8C (see Supplementary Table S3 for details). Added alkyl group is shown in bold in each case.

Br

O

+

PhLi

OO

O

O

5a

4

3

1aConditions

Conditions: Pd[P(tBu)3]2Pd2(dba)3 2.5 mol%, P(tBu)3

5 mol%

7.5 mol%

1.2 equiv.

Conversion 5a:3:4

Toluene, 1 h

70% 90:–:10

Full 98:–:2

Figure 2 | Cross-coupling of phenyllithium and 4-methoxy-bromobenzene.

Optimization of the synthesis of biaryl 5a and possible side products arising

from a halogen–lithium exchange (3) and a homocoupling reaction (4).

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is important to note that 5a could be obtained in 93% yield with totalselectivity when the reaction was carried out starting with 5.5 mmol(1.029 g) of 1a using 1 mol% of the catalyst. Remarkably, the presenceof an acidic proton, as in the case of 5-bromo-indole, was tolerated,providing 5-phenylindole 5e in 89% yield. In this case, 3 equiv. ofPhLi were necessary to reach full conversion.

Heterocyclic lithium compounds are also successful couplingpartners. In the case of thienyllithium the reduced reactivity ofthis organometallic reagent required the use of tetramethylethylene-diamine (TMEDA) as activating agent and a slightly higher temp-erature (up to 40 8C, 1 h). Under these conditions, correspondingproducts 5f and 5g were obtained in 81% and 88% yield withelectron-poor and electron-rich arylbromides, respectively. TheC(sp2)–C(sp2) cross-coupling was also extended to the reaction ofalkenylbromides with aryllithium, providing tetrasubstituted aryl-alkene 5h and thiophene-substituted Z-olefin 5i in high yields.Again, 1H-NMR analysis revealed that the olefin geometry was pre-served. Moreover, a sterically hindered ortho-substituted arylbro-mide such as 2,3-dimethyl-bromobenzene could be coupled inhigh yield and without loss of selectivity (5j). The versatility andmild conditions of the cross-coupling prompted us to examine thecompatibility with currently available procedures to access aryl-lithium species. In Table 3, the various sources of the aryllithium

reagents are highlighted; these include commercially available orga-nolithium reagents, those prepared via halogen–metal exchange,and organolithium compounds synthesized by direct metallation.The Pd-catalysed coupling reaction of various aryllithium com-pounds, by exploiting the halogen–lithium exchange reaction start-ing with arylbromides, showed that a range of substitutedaryllithium compounds can be applied (Table 3, 5k–5n). An intri-guing result is that the very hindered bis-ortho-substituted2,6-dimethyl-phenyllithium undergoes cross-coupling with elec-tron-rich 4-methoxy-bromobenzene to provide biaryl 5k in 90%yield without the need to increase the temperature, reactiontime or catalyst loading, while the presence of the even more elec-tron-donating 4-N,N-dimethylamino- moiety still provides thecorresponding biaryl 5l in good yield. An illustrative example ofthe direct metallation method is the highly selective and fast coup-ling of furyllithium, obtained by direct lithiation of furan,which provides p-methoxy- and p-chloro-substituted compounds5o and 5p in high yields. Having identified extremely mild con-ditions for heteroaryl–aryl cross-coupling we examined the mostwidely used method in synthesis for ortho-functionalization ofarenes, which is based on organolithium reagents obtainedthrough directed ortho-lithiation35. As shown in Table 3, methoxy-methyl (MOM)-protected phenol was converted in the

Table 3 | Scope of Pd-catalysed cross-coupling of aryllithium reagents.

Toluene, r.t.Ar–Br + Ar–Ar'

51

Ar'Li

Pd2(dba)3 2.5 mol%P(tBu)3 7.5 mol%

Organolithium source Products

O N NH

Cl

5a, 84% (93%)*

O

SS

F3C

5b, 80% 5d, 83% 5e, 89%5c, 85%

5f, 81%† † ‡ †,§5h, 81%5g, 88%

Commercial

SLi

Li

O

O N

5m, 71%5k, 90% 5l, 75% 5n, 80%

OHalogen-lithium exchange

Br

R

R–Li

R

Li

O

O

Cl

O

OOMOM

5o, 84% 5p, 88% 5q, 86%

Directed metallation

DMG

R–Li

DMG

Li

O O

Li

5j, 84%

OMOM

5r, 82%

CF3

S

5i, 99%

Conditions: bromide (0.3 mmol), ArLi (0.45 mmol, diluted with THF to reach 0.60 M concentration and added over 1 h), Pd2(dba)3 2.5 mol%, P(tBu)3 7.5 mol%, toluene (2 ml) at room temperature.Selectivity .95% in all cases.Yield values refer to isolated yields after purification.DMG, directing metallation group. Added aryl group is shown in bold in each case.*Yield in brackets refers to the 1 g scale reaction using 1 mol% of catalyst.†Reaction performed using TMEDA (1.2 equiv.) at 40 8C.‡Reaction performed on a 1.5 mmol scale.§Gas chromatography yield: single product (see Supplementary Information, page S20 for details).

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ortho-lithiated reagent using n-BuLi, and subsequent Pd-catalysedcoupling with p-methoxybenzene provided the correspondingortho-para-di-substituted biaryl 5q in 86% yield. A similar selectiv-ity was observed when this ortho-lithiated reagent was coupled with2-bromonaphthalene (5r).

Applicability of the Pd-catalysed cross-coupling withorganolithium reagents. Finally, we compared the Pd-catalysedcross-coupling of alkyl- and aryllithium reagents with someestablished methods, as shown for representative alkylations andarylations currently used in the production of building blocks inpharmaceutical and materials chemistry (Fig. 3). The first exampleinvolves direct aryl–alkylation with organolithium in thepreparation of 3,5-dichlorobutylbenzene, a key intermediate inthe synthesis of an S1P5 receptor agonist, a potential drug for thetreatment of cognitive disorders36. The reaction of 1-bromo-3,5-dichlorobenzene with n-BuLi in toluene in the presence of5 mol% Pd[P(tBu)3]2 provided the cross-coupled product 2z in86% yield. Although organoboron compounds have proven to behighly versatile and chemoselective reagents for cross-couplingreactions37, the lower reactivity of alkyl boron reagents usuallyrequires more severe coupling conditions. The dramatic differencein reaction conditions should be noted when comparing thecurrent procedure, based on the organofluoroborate compound as acoupling partner, to reach the same yield of target compound andusing the same catalyst loading (48 h at 90 8C versus 1 h at 20 8C).The versatility of the aryl–aryl cross-coupling is also illustrated inthe synthesis of the bis-thienyl-fluorene derivative 5s, a member ofa family of widely used oligoarene building blocks in thepreparation of optoelectronic organic materials38,39. Pd-catalysedtwofold arylation of representative bis-bromo-dialkylfluorene with2-thienyllithium provides rapid access to the target compound 5sin high yield, with both product formation and reaction conditionsagain comparing highly favourably with existing syntheticmethodology (40 8C, 1 h, 85% yield when 2-thienyllithium is usedversus 90 8C, 24 h, 73% yield for tributyl(thiophen-2-yl)stannane).

Comparing the direct alkylation and arylation using the lithiumreagents with the organoboron- and stannous-based variants shownin Fig. 3, the most prominent features are the short reaction timesand very mild reaction temperatures, while still maintaining highyields. It should be noted that, although used in myriad cross-

couplings and with organoboranes showing high functional grouptolerance, some of the B- or Sn-based methods need an additionalreaction step to prepare the organometallic partner, frequently start-ing from the corresponding organolithium reagents. Organolithiumreagents are highly reactive, but the fact that they are easy accessible,among the cheapest of organometallic reagents commercially avail-able, with well-established methodology for safe handling, has con-tributed to their widespread use in synthetic chemistry. Despite thetremendous success of cross-coupling, complementary methodsthat are concise and selective, avoid toxic waste, and featureimproved step- and atom-economy are highly warranted. Theexamples shown in Fig. 3 illustrate how, through the use of organo-lithium reagents, the need to prepare the Sn or B reagents might beavoided, the sometimes notorious problems with purification (com-plete removal of toxic and nonpolar Sn side products) are elimi-nated, the amount of waste products is drastically reduced(Fig. 3a; the atom efficiency to prepare 2z is 67% using n-BuLiversus 17% using potassium n-butyl trifluoroborate) and excessbase (for example, 3 equiv. Cs2CO3) is not required.

ConclusionIn summary, we have developed a fast and highly selective methodfor the direct catalytic cross-coupling of alkyl- and (hetero)aryl-lithium reagents. The reaction takes place under mild conditionswith a broad scope of alkenyl and (hetero)aryl bromides. Severalfunctional groups, including halides, acetals, ethers, amines andalcohols, as well as acidic protons, are tolerated. Although this pro-tocol is not compatible with ketones or nitriles, we have shown in apreliminary study that ester moieties can be used with good selectiv-ity. The results from the present study have demonstrated thatPd-catalysed cross-coupling of cheap and readily available alkyl-and aryllithium reagents represents a valuable alternative for themild, selective and atom-economic formation of C–C bonds forthe construction of building blocks for biologically active com-pounds and organic materials.

MethodsGeneral procedure for the Pd-catalysed cross-coupling with alkyllithiumreagents. (Caution! Some organolithium reagents can be pyrophoric.) In a drySchlenk flask, Pd[P(t-Bu)3]2 (5 mol%, 0.015 mmol, 7.66 mg) and the substrate(0.3 mmol) were dissolved in 2 ml of dry toluene under an inert atmosphere. Thecorresponding lithium reagent (1.2 equiv.) was diluted with toluene to reach a

Cl

Cl

+

+

Br

M

Cross-coupling

Cl

Cl 2z

Cl

Cl

OO

NHO

O

S1P5 selective agonist

a

C8H17C8H17

S

S

5s

C8H17C8H17

Br

Br

S

M

Photo- and redox active polymers (OLEDs, photovoltaic devices,...)

b

Cross-coupling

Reported method

This work

M: BF3K (Mw: 106.96)Pd(dppf)Cl2·CH2Cl2, 5 mol%, Cs2CO3 (3 equiv.), toluene, 90 oC, 48 h. 85% yield

M: Li (Aw: 6.94)Pd[P(tBu)3]2, 5 mol%, toluene, r.t., 1 h. 86% yield

Reported method

This work

M: SnBu3 (Mw: 290.06)Pd(PPh3)4, 3 mol%, DMF, 90 oC, 24 h. 73% yield

M: Li (Aw: 6.94)Pd2(dba)3, 2.5 mol%, P(tBu)3 7.5 mol%TMEDA, (1.2 equiv.) toluene, 40 oC, 1 h. 85% yield

Figure 3 | Comparison of established methods and the present cross-coupling protocol with organolithium reagents. a, Synthesis of key intermediates for

an S1P5 receptor agonist compared with the reported procedure using butyl potassium trifluoroborate36. b, Synthesis of optoelectronic polymers, compared

with the reported Stille coupling38,39. These examples illustrate how the use of the corresponding organolithium reagents allows the reactions to proceed

under milder conditions, with shorter reaction times and with a reduction in waste. TMEDA, tetramethylethylenediamine; DMF, N,N-dimethyl formamide.

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concentration of 0.36 M. This solution was slowly added over 1 h using a syringepump. After the addition was completed, a saturated aqueous solution of NH4Cl wasadded and the mixture was extracted three times with diethyl ether. The organicphases were collected, and solvent evaporation under reduced pressure afforded thecrude product, which was then purified by column chromatography.

General procedure for the Pd-catalysed cross-coupling with aryllithium reagents.In a dry Schlenk flask, Pd2(dba)3 (2.5 mol%, 0.0075 mmol, 6.87 mg) and P(t-Bu)3(7.5 mol%, 0.0225 mmol, 4.55 mg) were dissolved in toluene and the substrate(0.3 mmol) was added under an inert atmosphere. The corresponding aryllithiumreagent (1.5 equiv.) was diluted with THF to reach a concentration of 0.6 M (unlessotherwise specified); this solution was slowly added over 1 h using a syringe pump.After the addition was completed, a saturated solution of aqueous NH4Cl was addedand the mixture was extracted three times with diethyl ether. The organic phaseswere collected, and solvent evaporation under reduced pressure afforded the crudeproduct, which was then purified by column chromatography.

Additional experimental procedures, descriptions of compounds and analyticalmethods are given in the Supplementary Information.

Received 14 December 2012; accepted 3 May 2013;published online 9 June 2013; corrected online 17 June 2013

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AcknowledgementsThe authors thank the Netherlands Organization for Scientific Research (NWO-CW), theNational Research School Catalysis (NRSC-C) and the European Research Council (ERCadvanced grant 227897 to B.L.F.) for financial support.

Author contributionsM.G. and M.F.-M. performed the experiments. M.G., M.F.-M. and B.L.F. designed theexperiments, analysed the data and wrote the manuscript. B.L.F. guided the research.

Additional informationSupplementary information and chemical compound information are available in theonline version of the paper. Reprints and permissions information is available online atwww.nature.com/reprints. Correspondence and requests for materials should be addressedto B.L.F.

Competing financial interestsThe authors declare no competing financial interests.

ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.1678

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