364 Chem. Commun., 2013, 49, 364--366 This journal is c The Royal Society of Chemistry 2013

Cite this: Chem. Commun.,2013, 49, 364

Single electron transfer-induced Grignardcross-coupling involving ion radicals asexclusive intermediates†

Nanase Uchiyama,a Eiji Shirakawa*a and Tamio Hayashi*b

The mechanism of the previously developed cross-coupling reac-

tion of aryl Grignard reagents with aryl halides was explored in

more detail. Single electron transfer from an aryl Grignard reagent

to an aryl halide initiates a radical chain by giving an anion radical

of the aryl halide. The following propagation cycle consists entirely

of anion radical intermediates.

Cross-coupling of arylmetals with aryl halides is one of themost straightforward and reliable methods to obtain biaryls, inwhich transition metal catalysts have inevitably been used.1 Onthe other hand, we have recently reported the first transitionmetal-free coupling of arylmagnesium bromides (Ar1–MgBr)with aryl halides (Ar2–X) (eqn (1)), utilizing activation ofAr2–X by single electron transfer (SET).2 We proposed an SRN1mechanism,3 shown as path A in Scheme 1. Thus, SET fromAr1–MgBr to Ar2–X gives [Ar2–X]�� (step a), which is convertedto Ar2� upon elimination of X� (step b). After nucleophilicattack of Ar1–MgBr on Ar2� (step c), SET from the resulting[Ar1–Ar2]�� to Ar2–X gives the coupling product Ar1–Ar2 andregenerates [Ar2–X]�� to reenter the radical chain (step d).4 Wedisclosed that addition of an anion radical of a biaryl as a singleelectron equivalent drastically accelerates the reaction, and thataryl halides show higher reactivities when they have lowerreduction potentials. These results support that the reactionpathway includes SET as in steps a and d,5 but elucidation ofthe rest of the steps (b and c) is left unexplored. Here we reportwhat intermediates are involved in the Grignard cross-coupling,where [Ar2–X]�� is transformed not to Ar2� but directly to[Ar1–Ar2]��, as shown in path B in Scheme 1.6

ð1Þ

The cross-coupling we developed gives biaryls in highyields.2 For example, the reaction of PhMgBr (1a: 1.5 equiv.)with 2-iodonaphthalene (2m) in toluene in the presence of THF(6 equiv.) at 110 1C for 24 h gave 97% yield of 2-phenylnaphthalene(3am) (eqn (2)).7 The yield was reasonably high but GC analysis ofthe reaction mixture showed existence of a trace amount (0.3%) ofa regioisomeric mixture of 2-naphthyltoluenes (4: o/m/p = 63/22/15),which is likely to be produced by addition of the 2m-derivednaphthyl radical to toluene. The characteristic high ortho-selectivity strongly supports involvement of the radical additionto the benzene ring.8 The generation of Ar2� from Ar2–X in thereaction mixture is consistent with operation of the SRN1mechanism (path A of Scheme 1) on condition that arylradicals (Ar2�) react preferentially with aryl Grignard reagents(Ar1–MgBr). This requirement seemed to be readily fulfilled,considering that the resulting anion radicals, [Ar1–Ar2]��, aremuch more stable than [ArNH2]��, which are reported to beinvolved as intermediates in the SRN1 reaction.9 However, thereaction of an aryl radical precursor with an aryl Grignardreagent gave a contradictory result. Thus, treatment ofphenylazo(triphenyl)methane (PAT), which is known togenerate Ph� upon heating,10 with p-methoxyphenylmagnesiumbromide (1b) in toluene gave 4-methoxybiphenyl (5) only in 2%yield, along with a regioisomeric mixture (o/m/p = 63/23/14) ofmethylbiphenyls (6) as a major product (25% yield) (eqn (3)).11

The result shows that aryl radicals react much preferentially

Scheme 1

a Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto,

606-8502, Japan. E-mail: shirakawa@kuchem.kyoto-u.ac.jpb Institute of Materials Research and Engineering, 3, Research Link, 117602,

Singapore. E-mail: tamioh@imre.a-star.edu.sg

† Electronic supplementary information (ESI) available: Experimental procedureand spectral data. See DOI: 10.1039/c2cc37643a

Received 20th October 2012,Accepted 15th November 2012

DOI: 10.1039/c2cc37643a

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This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 364--366 365

with a solvent amount of toluene over with aryl Grignardreagents,12 and thus the Ar2� derived from Ar2–X is unlikelyto be involved in the cross-coupling reaction.

ð2Þ

ð3Þ

No involvement of aryl radical intermediates was furtherconfirmed by a radical clock reaction using 2-(3-butenyl)phenyliodide (2n), the corresponding aryl radical of which is known toreadily cyclize (kc = 5 � 108 s�1 at 50 1C).13 The reaction of 2nwith 1a gave no cyclization products but a direct phenylationproduct, 3an (eqn (4)). Considering the observation that arylradicals do not react smoothly with aryl Grignard reagents, noproduction of cyclization products supports no involvement ofaryl radicals.14

ð4Þ

Taking into account the previous conclusion that SET toAr2–X to give [Ar2–X]��, as steps a and d in Scheme 1, isoperative, no participation of Ar2� implies that [Ar2–X]�� reactsdirectly with Ar1–MgBr as shown in step e in Scheme 1.15 In thisevent, the kind of X possibly affects the reaction with arylGrignard reagents. This holds true, thus in competition reac-tions between tolylmagnesium bromides 1c and 1d, both2-naphthyl iodide (2m) and chloride (20m) reacted preferen-tially with less hindered p-tolyl derivative 1c, where the selec-tivity was considerably higher in the reaction of 20m (74 : 26)than in that of 2m (62 : 38) (Scheme 2).16–18

In the previous report,2 we demonstrated the involvement ofanion radical intermediates by the fact that addition of a similar

anion radical accelerates the reaction. Thus, the yield in thereaction of PhMgBr (1a) with unreactive 2-bromonaphthalene(200m) at 80 1C for 12 h was increased from 1% (2% conv.) to 80%(98% conv.) by addition of lithium di-tert-butylbiphenylide(LDBB: 0.2 equiv.). In contrast, almost no reaction (2% conv.,o1% yield) took place in the presence of PAT (0.2 equiv.), wherethe generated phenyl radical was converted mainly to methyl-biphenyls (6).19 The result is rationally understood as thatacceleration is possible with addition of an anion radical inter-mediate but not with addition of an aryl radical, which is not anintermediate.

In this cross-coupling, an oxidative homocoupling product(Ar1–Ar1) of Ar1–MgBr is always produced in a small but certainamount.20 In the previous report, we took this result as a proofthat SET from Ar1–MgBr to Ar2–X is operative in the initiationstep (a in Scheme 1), considering that Ar1–Ar1 is producedthrough fragmentation of [Ar1–MgBr]�+, followed by the reac-tion of the resulting Ar1� with Ar1–MgBr. However, an isomericmixture of Ar1–C6H4Me is produced only in a much less amountthan Ar1–Ar1.21 Taking into account that aryl radicals reactpreferentially with a solvent amount of toluene over with arylGrignard reagents (eqn (3)), this result shows that Ar1� isgenerated only in a trace amount. Consequently, Ar1–Ar1 islikely to be produced by the reaction of [Ar1–MgBr]�+ withAr1–MgBr in a similar manner to the production of Ar1–Ar2

from the reaction of [Ar2–X]�� with Ar1–MgBr.Aryl Grignard reagents are known to act as single electron

donors toward certain electrophiles.22 For example, SET fromPhMgBr (1a) to cinnamyl chloride (7) to give [PhMgBr]�+ and[7]��, respectively, is reported to take place during substitutionreaction between 1a and 7.22b In this report, homocouplingproducts (9 and 90) of 7 are regarded as end products ofintermediate [7]��, but the course of cation radical [PhMgBr]�+

is not disclosed. Then we conducted the reaction in our hands,paying attention to the course of [PhMgBr]�+ (Scheme 3). Thereaction of 1a (0.60 mmol) with 7 (0.20 mmol) under thereported conditions gave Ph–Ph (10) in an amount (0.048 mmol)comparable to that (0.044 mmol) of 9/90 in addition to sub-stitution product 8. The yields of 10 and 9/90 were increased byuse of the solvent system (toluene with 6 equiv. of THF) in thecross-coupling, giving no methylbiphenyls (6). No productionof methylbiphenyls when using toluene as a solvent shows thatPh� is not present in the reaction mixture. Consequently,[PhMgBr]�+, with no fragmentation to Ph� and [MgBr]+, reactswith PhMgBr to give Ph–Ph via [Ph–Ph]��. It is most likelythat Ph–Ph is also produced in the same manner as that in

Scheme 2 Scheme 3

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366 Chem. Commun., 2013, 49, 364--366 This journal is c The Royal Society of Chemistry 2013

our cross-coupling and thus SET from aryl Grignard reagents toaryl halides is operative.

All these results are compiled into a mechanism shown inScheme 4, exemplified by the reaction of PhMgBr (1a) with2-iodonaphthalene (Np–I: 2m). The whole scheme consists ofthree SETs toward Np–I giving [Np–I]�� and two C–C bondforming reactions (BFR) of PhMgBr with an ion radical. Twosingle electrons generated at the expense of two PhMgBr in theinitiation step are handed over to Np–I to give [Np–I]��, andthen promote the propagation cycle.

In conclusion, we have revealed that the transition metal-free coupling of Ar1–MgBr with Ar2–X is initiated by SET fromAr1–MgBr to Ar2–X and propagated by a scheme consisting ofthe reaction of the resulting [Ar2–X]�� with Ar1–MgBr and SETfrom [Ar1–Ar2]�� to Ar2–X. No involvement of Ar2�, which wouldinduce side reactions such as hydrogen abstraction from solventsand addition to benzene rings, is likely to contribute to highselectivity and thus high yields of the cross-coupling.

This work has been supported financially in part by Grant-in-Aid for Scientific Research on Innovative Areas ‘‘MolecularActivation Directed toward Straightforward Synthesis’’ (23105521to E.S.) from the Ministry of Education, Culture, Sports, Scienceand Technology of Japan. N.U. thanks the JSPS for a ResearchFellowship for Young Scientists.

Notes and references1 For reviews, see: J. Hassan, M. Sevignon, C. Gozzi, E. Schulz and

M. Lemaire, Chem. Rev., 2002, 102, 1359–1469; Metal-CatalyzedCross-Coupling Reactions, ed. A. de Meijere and F. Diederich,Wiley-VCH, Weinheim, 2nd edn, 2004, vol. 1–2.

2 E. Shirakawa, Y. Hayashi, K. Itoh, R. Watabe, N. Uchiyama, W. Konagaya,S. Masui and T. Hayashi, Angew. Chem., Int. Ed., 2012, 51, 218–221.

3 For reviews on SRN1 reactions, see: J. F. Bunnett, Acc. Chem. Res.,1978, 11, 413–420; R. A. Rossi, A. B. Pierini and A. B. Penenory,Chem. Rev., 2003, 103, 71–167.

4 Various anionic nucleophiles such as enolates and thiolates act asreaction partners of Ar2� in SRN1 reaction but arylmetals have neverbeen used, see ref. 3. The reaction of Grignard reagents (R–MgX)including arylmagnesium bromides with tert-alkyl halides (R0–X) togive R–R0 is reported to involve SET from R–MgX to R0–X. However,the coupling is considered to proceed not through the SRN1 mecha-nism but through radical coupling between the resulting R� and R0�.M. Ohno, K. Shimizu, K. Ishizaki, T. Sasaki and S. Eguchi, J. Org.Chem., 1988, 53, 729–733.

5 The possibilities that the cross-coupling reaction proceeds throughtransition metal catalysis, aryne intermediates, or nucleophilicaromatic substitution are excluded from the considerationsdescribed in the previous report (ref. 2).

6 This kind of mechanism, which includes the reaction of anionradicals of aryl halides with anionic nucleophiles, has sometimesbeen called as the SRN2 mechanism in comparison with the

SRN1 mechanism, which includes aryl radical intermediates. Therehave been debates as to which one is operative. For an example ofthe debates, see: D. B. Denney and D. Z. Denney, Tetrahedron, 1991,47, 6577–6600; J. F. Bunnett, Tetrahedron, 1993, 49, 4477–4484;R. A. Rossi and S. M. Palacios, Tetrahedron, 1993, 49, 4485–4494.

7 We used the same magnesium turnings and toluene as those usedin the previous report. For their ICP analysis, see ref. 2.

8 Addition of aryl radicals to benzene rings is known to lead to biarylsthrough homolytic aromatic substitution (HAS), where both electron-donating and -withdrawing substituents on the benzene ring accel-erate the addition, especially to their ortho-positions. For recentreviews on HAS, see: A. Studer and M. Bossart, in Radicals in OrganicSynthesis, ed. P. Renaud and M. P. Sibi, Wiley-VCH, Weinheim,2001, ch. 1.4, vol. 2, pp. 62–80; W. R. Bowman and J. M. D. Storey,Chem. Soc. Rev., 2007, 36, 1803–1822.

9 J. K. Kim and J. F. Bunnett, J. Am. Chem. Soc., 1970, 92, 7463–7464;J. K. Kim and J. F. Bunnett, J. Am. Chem. Soc., 1970, 92, 7464–7466.See also ref. 3.

10 PAT is known to undergo decomposition into Ph�, N2, and Ph3C� intoluene at 60 1C. (a) G. A. Russell and R. F. Bridger, Tetrahedron Lett.,1963, 4, 737–740; (b) T. Suehiro, A. Suzuki, Y. Tsuchida andJ. Yamazaki, Bull. Chem. Soc. Jpn., 1977, 50, 3324–3328.

11 Thermolysis of PAT in the absence of an aryl Grignard reagent(in toluene with 120 equiv. of THF, 110 1C, 1 h) gave 31%yield (o/m/p = 59 : 24 : 17) of 6. A similar result is reported inref. 10b.

12 Toluene : 1b is 47 : 1 in eqn (3), whereas toluene : 1 is 63 : 1 underthe standard cross-coupling conditions, e.g., in eqn (2).

13 A. N. Abeywickrema and A. L. J. Beckwith, J. Chem. Soc., Chem.Commun., 1986, 464–465; H. Yasuda, Y. Uenoyama, O. Nobuta,S. Kobayashi and I. Ryu, Tetrahedron Lett., 2008, 49, 367–370. Weconducted reduction of 2n in toluene (0.2 M, 110 1C, 1 h) withBu3SnH (1.3 equiv.) in the presence of AIBN (0.1 equiv.) to give 70%yield of cyclization products (1-methylindane and 1,2,3,4-tetrahydro-naphthalene, 93 : 7) with 7% yield of the simple reduction product(4-phenyl-1-butene).

14 Generation of cyclization products in a similar radical clock reactionwas used as a support for exclusion of the SRN2 mechanism.A. L. J. Beckwith and S. M. Palacios, J. Phys. Org. Chem., 1991, 4,404–412.

15 The lifetime of [Ar2–X]�� is reported to be too short to reactwith some substrates due to fast fragmentation of [Ar2–X]�� intoAr2� and X�. However, only the data in the reaction in polar solventssuch as N-methylpyrrolidone and N,N-dimethylformamide areavailable. For recent examples, see: C. Costentin, M. Robert andJ.-M. Saveant, J. Am. Chem. Soc., 2004, 126, 16051–16057; N. Takeda,P. V. Poliakov, A. R. Cook and J. R. Miller, J. Am. Chem. Soc., 2004,126, 4301–4309.

16 Transformation of [Ar2–X]�� into [Ar1–Ar2]�� possibly takes morethan one step. In any case, the reaction of Ar1–MgBr with [Ar2–X]��,not with Ar2�, should take place, though, at present, we do not haveany convincing experimental data and/or theoretical explanation asto how this process proceeds. We consider it to be an importantfuture subject to elucidate the mechanism of this process.

17 Low reactivity of 2-naphthyl chloride (20m) compared with that ofthe iodide (2m) is ascribed mainly to its low electron acceptorcharacter in steps a and d in Scheme 1.

18 The absence of the leaving group effect on the selectivity insimilar competition reactions is used as a proof for the SRN1mechanism C. Galli and J. F. Bunnett, J. Am. Chem. Soc., 1981,103, 7140–7147.

19 Methylbiphenyls (6) were produced in a yield (30% based on PAT)similar to that (31%) in the reaction in the absence of 1a and 200m.See ref. 11.

20 For example, in the reaction of 1a (0.30 mmol) with 2m (0.20 mmol)shown in eqn (2), the amount of biphenyl was determined to be0.010 mmol by GC analysis.

21 In the reaction of 1a with 2m shown in ref. 20, methylbiphenyls wereproduced in 0.0003 mmol (0.1% GC yield based on 1a, o/m/p =63/23/14), where the ratio of Ar1–C6H4Me : Ar1–Ar1 is 1 : 33.

22 For SET from aryl Grignard reagents to benzophenones, see:(a) K. Maruyama, Bull. Chem. Soc. Jpn., 1964, 37, 897–898 To tert-alkyl halides: ref. 4. To cinnamyl chlorides: (b) K. Muraoka,M. Nojima, S. Kusabayashi and S. Nagase, J. Chem. Soc., PerkinTrans. 2, 1986, 761–767.

Scheme 4

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