Direct Catalytic Cross-Coupling of Organolithium Compounds Giannerini, Massimo; Fananas Mastral, Martin; Feringa, Ben L

University of Groningen

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

Published in: Nature Chemistry

DOI: 10.1038/NCHEM.1678

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ARTICLES PUBLISHED ONLINE: 9 JUNE 2013 | DOI: 10.1038/NCHEM.1678

Direct catalytic cross-coupling of organolithium compounds Massimo Giannerini, Martı´nFan˜ana´s-Mastral and Ben L. Feringa*

Catalytic carbon–carbon bond formation based on cross-coupling reactions plays a central role in the production of natural products, pharmaceuticals, agrochemicals and organic materials. Coupling reactions of a variety of organometallic reagents and organic halides have changed the face of modern synthetic chemistry. However, the high reactivity and poor selectivity of 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-lithium reagents undergo selective cross-coupling with aryl- and alkenyl-bromides. The process proceeds quickly under mild conditions (room temperature) and avoids the notorious lithium halogen exchange and homocoupling. The preparation of key alkyl-, aryl- and heterobiaryl intermediates reported here highlights the potential of these cross-coupling reactions for medicinal chemistry and material science.

ransition metal-catalysed cross-coupling reactions for the Here, we report a practical method for the fast and highly selec- selective formation of C–C bonds enable the facile preparation tive direct cross-coupling of organolithium reagents under mild Tof myriad structurally diverse and complex molecules essential conditions, and with broad scope, using Pd catalysis. Catalytic for the development of modern drugs and organic materials1–4. C–C bond formation readily proceeds with alkyl-, aryl- and hetero- Typically, Pd or Ni catalysis is used with an organic halide, and aryl-lithium reagents, providing a versatile and mild alternative to an organometallic or main-group reagent as nucleophilic coupling existing protocols (Fig. 1b). partner1,5, although (directing-group based) coupling via C–H acti- vation has recently emerged as a possible alternative6–8. Although Results and discussions Stille (with organotin as the nucleophile)9,10, Suzuki–Miyaura (organo- We anticipated that, to achieve selective cross-coupling of arylbro- boron)11,12, Negishi (organozinc)1,13,14, Hiyama–Denmark (organo- mide and organolithium species, fast lithium–bromide exchange silicon)15,16 and Kumada (organomagnesium)17,18 couplings are has to be suppressed by efﬁcient transmetallation and the pro- well established (Fig. 1a), the direct application of organolithium motion of fast oxidative addition and subsequent reductive elimin- reagents (among the most reactive and commonly used reagents ation of the organic moieties by the Pd complex. We hypothesized in chemical synthesis19) in cross-coupling reactions remains a that competing lithium–bromide exchange might be prevented by formidable challenge. Some of the coupling partners are directly controlling the reactivity and aggregation state of the organolithium accessible; for instance, organoboron compounds can be prepared reagent by choosing an appropriate solvent, an approach we recently by hydroboration of unsaturated substrates20 (that is, alkyl and took in catalytic asymmetric allylic alkylations25. The high reactivity vinyl boranes) or by borylation of C–H bonds21 (alkyl and aryl of the organolithium species opens the exciting prospect of selective boranes). However, as aryl organoboron and organotin compounds, cross-coupling at room temperature by ﬁne-tuning of the in particular, are frequently prepared from the corresponding Pd-catalyst complex. lithium reagents, a concise method, taking advantage of the direct use of organolithium compounds in C–C bond formation, would a Well established methods:

eliminate the need for such additional transformations. Transition metal catalyst Organolithium reagents are cheap and either commercially available R1–X R+ 2–M R1–R2 or readily accessible through halogen–metal exchange or direct metallation. Early studies by Murahashi and co-workers22 on the X = halide or sulfonate use of organolithium reagents for cross-coupling reactions revealed Stille (M = Sn); Negishi (M = Zn); Suzuki-Miyaura (M = B); the limitations of this transformation due to the very high reactivity Hiyama-Denmark (M = Si); Kumada (M = Mg). of these organometallic compounds and also the high temperatures b required22. One major problem that has precluded the application of This work: M = Li organolithium reagents is the competing formation of homocoupled Pd catalyst R1–Br + R2–Li R1–R2 products as a result of fast lithium–halogen exchange preceding 1 h Pd-catalysed C–C bond formation. Recently, a Murahashi-type Room temperature biaryl coupling was performed using a ﬂow-microreactor23, while Selectivity >95% R1 = alkenyl, aryl, heteroaryl High yield in an alternative approach, a stoichiometric silicon-based transfer R2 = alkyl, aryl, heteroaryl agent was used24. However, the development of an efﬁcient catalytic protocol for cross-coupling of highly reactive organolithium species Figure 1 | Catalytic cross-coupling reactions. a, Established methodology that does not suffer from lithium–halogen exchange and homocou- based on organo-tin, -zinc, -boron, -silicon and -magnesium compounds. pling has proven elusive until now. b, Cross-coupling using organolithium compounds.

Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands. *e-mail: [email protected]

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ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.1678

Table1 | Cross-coupling of n-BuLi and 4-methoxy-bromobenzene.

Pd complex O O O Ligand 2a 3 1a Toluene, r.t. + O

nBuLi (1.2 equiv.) O O 4 2x Entry Pd complex Ligand Reaction time (h) Conversion (%) 2a:3:4:2x*

1Pd2(dba)3, 2.5 mol% XPhos, 10 mol% 3 Full 80:5:10:5 2 – – 3 25 –:.95:–:–

3Pd2(dba)3, 2.5 mol% – 3 22 23:48:29:– 4Pd2(dba)3, 2.5 mol% SPhos, 10 mol% 1 Full 89:5:6:– 5Pd2(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.

Pd-catalysed cross-coupling with alkyllithium reagents. For our cross-coupling reactions to enhance reductive elimination and initial model reaction (Table 1) we selected 4-methoxy- avoiding beta-hydrogen elimination (which is yet another bromobenzene, a reluctant arylhalide26 in many coupling competing pathway to the formation of dehalogenated and 31 t reactions, and n-BuLi, one of the most reactive organometallic isomerized products) , the ligand P( Bu)3 was also tested. The use t reagents, realizing that successful selective cross-coupling of these of the in situ formed complex from Pd2(dba)3 and P( Bu)3 gave compounds would mean access to an abundance of other rise to a selectivity comparable with those obtained with coupling partners. Using, under an inert atmosphere, 1.2 equiv. of dialkylbiaryl phosphines (Table 1, entry 5). When the 27 t n-BuLi, XPhos (10 mol%) as the ligand in combination with commercially available preformed complex Pd[P( Bu)3]2 (5 mol%) Pd2(dba)3 (2.5 mol%, ratio of Pd to ligand of 1:2), toluene as the was used instead of the in situ formed catalyst, cross-coupled solvent to avoid ethereal compounds capable of enhancing product 2a was obtained in high yield and with excellent halogen–metal exchange, with dilution (0.45 M) and slow selectivity, with minimal halogen exchange taking place while addition (3 h) of the lithium reagent to avoid excess completely inhibiting the formation of the homocoupling product organolithium reagent in solution, the reaction led to the 4 (Table 1, entry 6). Remarkably, the reaction also proceeds with predominant formation of the desired cross-coupling product 1 mol% of catalyst, with similar selectivity (Table 1, entry 7). p-methoxybutylbenzene 2a. Although full conversion is reached at With the optimal conditions for highly selective alkyl–aryl cross- room temperature, the presence of a small but significant amount coupling determined, the scope of the reaction of alkyllithium (5%) of dehalogenated product 3 (due to Br–Li exchange) and reagents and arylbromides was examined (Table 2). homocoupled biaryl product 4 (10%), as well as a small amount The Pd-catalysed coupling of alkyllithium compounds with aryl- (5%) of the isomerized cross-coupling product 2x, illustrates the bromides entails substrates bearing halide, alcohol, acetal and ether manifold competing pathways (Table 1, entry 1). In a few specific functionalities, electron-withdrawing chlorides and electron-donat- cases, such as the reaction between bromobenzene and n-BuLi in ing methoxy and dimethylamine substituents (Table 2). With tetrahydrofuran (THF)28, the coupling product is obtained in the p-chloro-bromobenzene, coupling occurs, as expected, exclusively absence of a metal complex as a result of halogen–metal exchange at the bromine-substituted carbon, but with no detectable chloride and subsequent alkylation of the aryllithium. However, the displacement (2c). Polyaromatic compounds such as bromo- reaction with 1a using THF as solvent in the absence of Pd naphthalene are regioselectively alkylated at position 1 (2d)or2 catalyst gave incomplete conversion, affording a complex mixture (2e–2f), indicating that benzyne intermediates via 1,2-elimination of products (see Supplementary Table S1 for further details). are not formed. Remarkably, bromofluorene could be alkylated In toluene, the omission of the Pd catalyst resulted in low (2g,2h) using only 1.2 equiv. of the corresponding organolithium conversion and the exclusive formation of dehalogenated product reagent, despite the acidity of the benzylic protons (pKa ¼ 22). 3 (Table 1, entry 2). A dramatic drop in selectivity is observed The scope of this C(sp3)–C(sp2) cross-coupling also includes alkyl- under phosphine ligand-free conditions (Table 1, entry 3), lithium reagents ranging from the smallest MeLi (2f, 2h) to those implying that the nature of the phosphine ligand is a crucial bearing long alkyl chains (2i–2k). The cross-coupling of the functio- parameter27,29,30. Screening in situ prepared Pd catalysts with nalized lithium reagent trimethylsilylmethyllithium proceeds with different dialkylbiaryl phosphines29 (Supplementary Table S1) we excellent yields (2l–2o). Facile multiple coupling is illustrated with ′ found that the use of SPhos enhanced the selectivity towards 2, the twofold alkylation of 4,4 -bis-bromobiphenyl, providing 2p in completely suppressing the isomerization reaction while 91% yield. In addition, alkenyl bromides also undergo this cross- simultaneously shortening the addition time to 1 h (entry 4). coupling with high selectivity, as shown by the coupling between However, selectivity higher than 90% could not be achieved using 2-bromovinylbenzene and n-BuLi (2q) and (Z)-1-bromopropene this type of ligand (Supplementary Table S1). It should be noted and n-HexLi (2r). It is important to note that the stereochemical that the coupling reaction is remarkably fast at room temperature information is preserved and no olefin isomerization takes place and is finished upon complete addition of the organolithium during the reaction. Using this protocol, acetal-protected aldehydes reagent. As hindered trialkylphosphines30 are frequently used in were also tolerated (2s) without the interference of n-BuLi-mediated

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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1678 ARTICLES

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

t Pd[P( Bu)3]2 5 mol% Ar–Br + RLi Ar–R Toluene, r.t. 1 2

N O Cl

2a, 80% 2b, 88% 2c, 84% 2d, 92% 2e, 87% 2f, 83%

15 5 TMS 5 O O N O

2g, 88% 2h, 90% 2i, 88% 2j, 94% 2k, 95% 2l, 93%

Cl TMS TMS TMS

Ph S 5 Cl

2m, 97% 2n, 93% 2o, 87% 2p, 91% 2q, 89% 2r, 99%*

OH CO2Me

N O O O Cl

2s, 92% 2t, 61% 2u, 43%† 2v, 75% 2w, 78% 2x, 89% 2y, 79%

t 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( Bu)3]2 5 mol%, toluene (2 ml) at room temperature. Selectivity .95% in all cases, unless otherwise noted. Yield values refer to isolated yields after purification. *GC yield: product was not isolated due to volatility issues. † t Reaction carried out with the corresponding aryl iodide, 7.5 mol% Pd[P( Bu)3]2 at 210 8C (see Supplementary Table S3 for details). Added alkyl group is shown in bold in each case. cleavage of the protecting group. Remarkably, substrate 1t, bearing bearing secondary alkyl moieties32,33, without isomerization of the an unprotected hydroxyl group, could also be coupled with this alkyl moiety. The ease of coupling secondary alkyllithium reagents organolithium reagent (2 equiv.) to afford alcohol 2t in a good therefore came as a surprise; both i-PrLi and the more challenging yield. Although the use of ketone- or nitrile-containing substrates s-BuLi undergo Pd-catalysed coupling with arylbromides with elec- proved to be incompatible with this reaction, mainly due to the for- tron-donating and -withdrawing substituents in high yields, mation of 1,2-addition side products, compound 1u, bearing an showing no isomerization at all (2v–2y), presumably due to fast ester group, could be coupled with MeLi in moderate yield. In transmetallation–reductive elimination steps being inherent to this this case, it was necessary to use the corresponding aryl iodide catalytic system. and a lower temperature (210 8C) to achieve good selectivity (see Supplementary Table S3 for details). Pd-catalysed cross-coupling with (hetero)aryllithium reagents. A recurring challenge in the field of cross-coupling reactions is to With an efficient procedure for aryl–alkyl cross-coupling achieve selective C–C bond formation of organometallic reagents established, we turned our attention to aryl–aryl cross-coupling using arylbromides and aryllithium reagents (Fig. 2). Although the coupling of phenyllithium and 4-methoxybromobenzene 1a t Br proceeds in toluene at room temperature using Pd[P( Bu)3]2 as O catalyst, full conversion and selectivity was not achieved. Further O 3 optimization of the reaction conditions (Supplementary Table S2) Conditions 1a showed that full conversion was restored by using the in situ 34 t Toluene, 1 h O prepared catalyst using Pd2(dba)3 and P( Bu)3 as ligand. By + O 5a diluting the PhLi reagent in THF the selectivity was further PhLi enhanced, but traces of dehalogenated product appeared. In 1.2 equiv. accordance with our hypothesis, lowering the amount of THF O 4 eliminated this side reaction, and finally using 2.5 mol% Pd catalyst with a ligand to Pd ratio of 1.5:1 under optimized Conversion 5a:3:4 conditions resulted in biaryl formation (in 1 h at room t temperature) with excellent isolated yield and 98% selectivity (Fig. 2). Conditions: Pd[P( Bu)3]2 5 mol% 70% 90:–:10 t Pd2(dba)3 2.5 mol%, P( Bu)3 7.5 mol% Full 98:–:2 Studying the scope of biaryl formation via Pd-catalysed cross-coupling of a range of arylbromides and aryllithium reagents showed that at Figure 2 | Cross-coupling of phenyllithium and 4-methoxy-bromobenzene. 20 8C in 1 h the corresponding biaryls 5 are obtained in high yields Optimization of the synthesis of biaryl 5a and possible side products arising (Table 3). For example, electron-rich (5a,5b)andelectron-poor(5c) from a halogen–lithium exchange (3) and a homocoupling reaction (4). phenylbromides and naphthylbromide (5d) were readily arylated. It

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ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.1678

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

Pd2(dba)3 2.5 mol% t P( Bu)3 7.5 mol% Ar–Br + Ar'Li Ar–Ar' Toluene, r.t. 1 5 Organolithium source Products

Commercial

O N Cl N H 5a, 84% (93%)* 5b, 80% 5c, 85% 5d, 83% 5e, 89% Li S Li S S S F3C

5f, 81%† 5g, 88%† 5h, 81%‡ 5i, 99%†,§ 5j, 84%

CF3 Halogen-lithium exchange O

Br Li R–Li

O N R R O 5k, 90% 5n, 80% 5l, 75% 5m, 71%

Directed metallation DMG DMG O O

R–Li Li OMOM OMOM O O O Cl O Li 5o, 84% 5p, 88% 5q, 86% 5r, 82%

t 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( Bu)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). is important to note that 5a couldbeobtainedin93%yieldwithtotal reagents are highlighted; these include commercially available orga- selectivity when the reaction was carried out starting with 5.5 mmol nolithium reagents, those prepared via halogen–metal exchange, (1.029 g) of 1a using 1 mol% of the catalyst. Remarkably, the presence and organolithium compounds synthesized by direct metallation. of an acidic proton, as in the case of 5-bromo-indole, was tolerated, The Pd-catalysed coupling reaction of various aryllithium com- providing 5-phenylindole 5e in 89% yield. In this case, 3 equiv. of pounds, by exploiting the halogen–lithium exchange reaction start- PhLi were necessary to reach full conversion. ing with arylbromides, showed that a range of substituted Heterocyclic lithium compounds are also successful coupling aryllithium compounds can be applied (Table 3, 5k–5n). An intri- partners. In the case of thienyllithium the reduced reactivity of guing result is that the very hindered bis-ortho-substituted this organometallic reagent required the use of tetramethylethylene- 2,6-dimethyl-phenyllithium undergoes cross-coupling with elec- diamine (TMEDA) as activating agent and a slightly higher temp- tron-rich 4-methoxy-bromobenzene to provide biaryl 5k in 90% erature (up to 40 8C, 1 h). Under these conditions, corresponding yield without the need to increase the temperature, reaction products 5f and 5g were obtained in 81% and 88% yield with time or catalyst loading, while the presence of the even more elec- electron-poor and electron-rich arylbromides, respectively. The tron-donating 4-N,N-dimethylamino- moiety still provides the C(sp2)–C(sp2) cross-coupling was also extended to the reaction of corresponding biaryl 5l in good yield. An illustrative example of alkenylbromides with aryllithium, providing tetrasubstituted aryl- the direct metallation method is the highly selective and fast coup- alkene 5h and thiophene-substituted Z-olefin 5i in high yields. ling of furyllithium, obtained by direct lithiation of furan, Again, 1H-NMR analysis revealed that the olefin geometry was pre- which provides p-methoxy- and p-chloro-substituted compounds served. Moreover, a sterically hindered ortho-substituted arylbro- 5o and 5p in high yields. Having identified extremely mild con- mide such as 2,3-dimethyl-bromobenzene could be coupled in ditions for heteroaryl–aryl cross-coupling we examined the most high yield and without loss of selectivity (5j). The versatility and widely used method in synthesis for ortho-functionalization of mild conditions of the cross-coupling prompted us to examine the arenes, which is based on organolithium reagents obtained compatibility with currently available procedures to access aryl- through directed ortho-lithiation35. As shown in Table 3, methoxy- lithium species. In Table 3, the various sources of the aryllithium methyl (MOM)-protected phenol was converted in the

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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1678 ARTICLES a Reported method Cl M Cl Br M: BF3K ( w: 106.96) O Pd(dppf)Cl2·CH2Cl2, 5 mol%, O o Cl Cs2CO3 (3 equiv.), toluene, 90 C, 48 h. Cross-coupling Cl 85% yield Cl This work + 2z M: Li (A : 6.94) Cl S1P5 selective agonist w HO N t M Pd[P( Bu)3]2, 5 mol%, toluene, r.t., 1 h. O 86% yield b Reported method C H 8 17 C H M Br 8 17 M: SnBu3 ( w: 290.06) Pd(PPh3)4, 3 mol%, C8H17 o C8H17 DMF, 90 C, 24 h. Br S 73% yield Cross-coupling Photo- and redox active polymers S (OLEDs, photovoltaic devices,...) This work + M: Li (Aw: 6.94) 5s t S Pd2(dba)3, 2.5 mol%, P( Bu)3 7.5 mol% M 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 36 an S1P5 receptor agonist compared with the reported procedure using butyl potassium trifluoroborate . 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. ortho-lithiated reagent using n-BuLi, and subsequent Pd-catalysed couplings and with organoboranes showing high functional group coupling with p-methoxybenzene provided the corresponding tolerance, some of the B- or Sn-based methods need an additional ortho-para-di-substituted biaryl 5q in 86% yield. A similar selectiv- reaction step to prepare the organometallic partner, frequently start- ity was observed when this ortho-lithiated reagent was coupled with ing from the corresponding organolithium reagents. Organolithium 2-bromonaphthalene (5r). reagents are highly reactive, but the fact that they are easy accessible, among the cheapest of organometallic reagents commercially avail- Applicability of the Pd-catalysed cross-coupling with able, with well-established methodology for safe handling, has con- organolithium reagents. Finally, we compared the Pd-catalysed tributed to their widespread use in synthetic chemistry. Despite the cross-coupling of alkyl- and aryllithium reagents with some tremendous success of cross-coupling, complementary methods established methods, as shown for representative alkylations and that are concise and selective, avoid toxic waste, and feature arylations currently used in the production of building blocks in improved step- and atom-economy are highly warranted. The pharmaceutical and materials chemistry (Fig. 3). The first example examples shown in Fig. 3 illustrate how, through the use of organo- involves direct aryl–alkylation with organolithium in the lithium reagents, the need to prepare the Sn or B reagents might be preparation of 3,5-dichlorobutylbenzene, a key intermediate in avoided, the sometimes notorious problems with purification (com- the synthesis of an S1P5 receptor agonist, a potential drug for the plete removal of toxic and nonpolar Sn side products) are elimi- treatment of cognitive disorders36. The reaction of 1-bromo-3,5- nated, the amount of waste products is drastically reduced dichlorobenzene with n-BuLi in toluene in the presence of (Fig. 3a; the atom efficiency to prepare 2z is 67% using n-BuLi t 5 mol% Pd[P( Bu)3]2 provided the cross-coupled product 2z in versus 17% using potassium n-butyl trifluoroborate) and excess 86% yield. Although organoboron compounds have proven to be base (for example, 3 equiv. Cs2CO3) is not required. highly versatile and chemoselective reagents for cross-coupling reactions37, the lower reactivity of alkyl boron reagents usually Conclusion requires more severe coupling conditions. The dramatic difference In summary, we have developed a fast and highly selective method in reaction conditions should be noted when comparing the for the direct catalytic cross-coupling of alkyl- and (hetero)aryl- current procedure, based on the organofluoroborate compound as a lithium reagents. The reaction takes place under mild conditions coupling partner, to reach the same yield of target compound and with a broad scope of alkenyl and (hetero)aryl bromides. Several using the same catalyst loading (48 h at 90 8Cversus1hat208C). functional groups, including halides, acetals, ethers, amines and The versatility of the aryl–aryl cross-coupling is also illustrated in alcohols, as well as acidic protons, are tolerated. Although this pro- the synthesis of the bis-thienyl-fluorene derivative 5s,amemberof tocol is not compatible with ketones or nitriles, we have shown in a a family of widely used oligoarene building blocks in the preliminary study that ester moieties can be used with good selectiv- preparation of optoelectronic organic materials38,39. Pd-catalysed ity. The results from the present study have demonstrated that twofold arylation of representative bis-bromo-dialkylfluorene with Pd-catalysed cross-coupling of cheap and readily available alkyl- 2-thienyllithium provides rapid access to the target compound 5s and aryllithium reagents represents a valuable alternative for the in high yield, with both product formation and reaction conditions mild, selective and atom-economic formation of C–C bonds for again comparing highly favourably with existing synthetic the construction of building blocks for biologically active com- methodology (40 8C, 1 h, 85% yield when 2-thienyllithium is used pounds and organic materials. versus 90 8C, 24 h, 73% yield for tributyl(thiophen-2-yl)stannane). Comparing the direct alkylation and arylation using the lithium Methods reagents with the organoboron- and stannous-based variants shown General procedure for the Pd-catalysed cross-coupling with alkyllithium reagents. (Caution! Some organolithium reagents can be pyrophoric.) In a dry in Fig. 3, the most prominent features are the short reaction times Schlenk flask, Pd[P(t-Bu)3]2 (5 mol%, 0.015 mmol, 7.66 mg) and the substrate and very mild reaction temperatures, while still maintaining high (0.3 mmol) were dissolved in 2 ml of dry toluene under an inert atmosphere. The yields. It should be noted that, although used in myriad cross- corresponding lithium reagent (1.2 equiv.) was diluted with toluene to reach a

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ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.1678 concentration of 0.36 M. This solution was slowly added over 1 h using a syringe 22. Murahashi, S., Yamamura, M., Yanagisawa, K., Mita, N. & Kondo, K. pump. After the addition was completed, a saturated aqueous solution of NH4Cl was Stereoselective synthesis of alkenes and alkenyl sulfides from alkenyl halides added and the mixture was extracted three times with diethyl ether. The organic using palladium and ruthenium catalysts. J. Org. Chem. 44, 2408–2417 (1979). phases were collected, and solvent evaporation under reduced pressure afforded the 23. Nagaki, A., Kenmoku, A., Moriwaki, Y., Hayashi, A. & Yoshida, J. Cross- crude product, which was then purified by column chromatography. coupling in a flow microreactor: space integration of lithiation and Murahashi coupling. Angew. Chem. Int. Ed. 49, 7543–7547 (2010). General procedure for the Pd-catalysed cross-coupling with aryllithium reagents. 24. Smith, A., Hoye, A. T., Martinez-Solorio, D., Kim, W. & Tong, R. Unification of In a dry Schlenk flask, Pd2(dba)3 (2.5 mol%, 0.0075 mmol, 6.87 mg) and P(t-Bu)3 anion relay chemistry with the Takeda and Hiyama cross-coupling reactions: (7.5 mol%, 0.0225 mmol, 4.55 mg) were dissolved in toluene and the substrate identification of an effective silicon-based transfer agent. J. Am. Chem. Soc.134, (0.3 mmol) was added under an inert atmosphere. The corresponding aryllithium 4533–4536 (2012). reagent (1.5 equiv.) was diluted with THF to reach a concentration of 0.6 M (unless 25. Pe´rez, M. et al. Catalytic asymmetric carbon–carbon bond formation via allylic otherwise specified); this solution was slowly added over 1 h using a syringe pump. alkylations with organolithium compounds. Nature Chem. 3, 377–381 (2011). After the addition was completed, a saturated solution of aqueous NH4Cl was added 26. Denmark, S. E., Smith, R. C., Tau, W. T. & Muhuhi, J. M. 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Borylation and silylation of C–H bonds: a platform for diverse Competing financial interests C–H bond functionalizations. Acc. Chem. Res. 45, 864–873 (2012). The authors declare no competing financial interests.

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