Regioselectivity in the aryne cross-coupling of aryllithiums with functionalized 1,2-dibromobenzenes

FULL PAPER

DOI: 10.1002/ejoc.201001283

Regioselectivity in the Aryne Cross-Coupling of Aryllithiums with

Functionalized 1,2-Dibromobenzenes

Vincent Diemer,^[a]Manon Begaud,^[a]Frédéric R. Leroux,*^[a]and Françoise Colobert^[a]

Keywords: Arynes / Cross-coupling / Bromine / Biaryls / Regioselectivity / Lithiation

Tri- and tetrasubstituted ortho-bromobiaryls have been syn-

thesized in good-to-excellent yields by aryne cross-coupling

reactions starting from 1,3-dimethoxybenzene and function-

alized 1,2-dibromobenzenes. This study outlines the influ-

ence of the 1,2-dibromobenzene precursor as well as the re-

action temperature on the outcome of the aryl–aryl bond for-

mation and indicates, in the case of dissymmetrical benzyne

precursors, how structural parameters (electronic effects, ste-

ric hindrance, temperature, etc.) control the regioselectivity

of the aryne cross-coupling reactions.

sient benzyne adds the aryllithium derivative, which is fol-

lowed by in situ transfer of bromine between the resulting

2-biaryllithium intermediate and another molecule of 1,2-

dibromobenzene. Mono-, di-, or even tetrasubstituted or-

tho-bromobiaryls can be obtained on gram scale (Figure 1).

The most impressive application of this methodology has

been the preparation by Milne and Buchwald of one of the

most versatile ligands (S-Phos) for the Suzuki–Miyaura

coupling reaction.^[14]The advantage of these ortho-bromo-

biphenyls lies in the possibility of functionalizing common

precursors by regioselective bromine/lithium permuta-

tions^[15]to give a large family of target ligands.^[16]

Introduction

Substituted biphenyls are important moieties with vari-

ous applications. In particular, biaryl substructures are of

general interest in pharmaceuticals and agrochemicals.^[1]In

addition, they have widespread applications as ligands in

catalysis and materials science.^[2]Biaryls are most fre-

quently prepared by transition-metal-catalyzed reactions,

for example, the palladium-catalyzed coupling of aryl ha-

lides or pseudo halides with arylboronic acids (Suzuki–Mi-

yaura reaction).^[3]Although this method is well established,

alternatives are being investigated to avoid the use of ex-

pensive transition metals or ligands especially required for

the coupling of deactivated or sterically hindered substrates.

Arynes have attracted widespread interest in organic syn-

thesis in recent years. Their chemistry was reviewed in 2003

by Pellissier^[4]and in 2008 by Sanz.^[5]They react with a

variety of N-, S-, O-, and Se-nucleophiles^[6]and, as recently

shown, with P-nucleophiles^[7]as well as with carbanions in

addition reactions.^[8]With alkenes they undergo Diels–Al-

der-type cycloaddition reactions,^[9][2+2] cycloadditions,^[10]

and 1,3-dipolar cycloadditions.^[11]Transition-metal-cata-

lyzed reactions using benzynes as the substrate have re-

cently become a powerful tool in organic synthesis.^[12]

Some cases of aryl–aryl coupling based on arynes have

been reported in the literature.^[13]Our group reported re-

cently on the efficient coupling of organolithium intermedi-

ates with arynes, the so-called “aryne coupling” reac-

tion.^[8a,8b]This methodology involves the formation of a

thermodynamically stable aryllithium intermediate and its

subsequent reaction with 1,2-dibromobenzene. The tran-

Figure 1. “Aryne coupling” yielding ortho-bromobiaryls.

Unfortunately, the use of this protocol had been restric-

ted to accessing suitable “aryne precursors”. Only a few

functionalized 1,2-dibromobenzenes have been described in

the literature or were accessible. Very recently our group

overcame these restrictions and developed a straightforward

access to 1,2-dibromobenzenes that could be functionalized

at will at any vacant position.^[17]

[a] CNRS et Université de Strasbourg (ECPM),

UMR CNRS 7509,

25 rue Becquerel, 67087 Strasbourg, France

Fax: +33-3-68852742

E-mail: frederic.leroux@unistra.fr

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201001283.

Eur. J. Org. Chem. 2011, 341–354

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V. Diemer, M. Begaud, F. R. Leroux, F. Colobert

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However, in contrast to the addition of an aryllithium

precursor to a symmetrical benzyne, we have now studied

the regioselectivity of the addition to dissymmetrical

benzynes (Figure 2) and found reaction conditions that al-

low “aryne” coupling with complete control of regioselec-

tivity. These results will be reported in this paper.

Results and Discussion

Aryne Cross-Coupling Reaction with Symmetrically

Substituted 1,2-Dibromobenzenes

As described by Buchwald and co-workers,^[18]2,6-di-

methoxyphenyllithium and 1-bromo-2-chlorobenzene af-

forded after aryne coupling in THF at 0 °C 2-bromobiaryl

2a in 81% yield. Analogously, 2a was obtained in 59% yield

after simple crystallization from MeOH, starting from

1,2-dibromobenzene (Table 1, entry 1). When the cross-

coupling reaction was performed at lower temperatures

(Table 1, entries 2 and 3), the conversion into 2a decreased

in favor of 2-bromo-1,3-dimethoxybenzene (3), a result of

a simple bromine/lithium permutation between 2,6-dimeth-

oxyphenyllithium and 1,2-dibromobenzene (1a; Scheme 1).

This competitive reaction, which was observed in all cases,

can be avoided by adjusting the reaction temperature de-

pending on the substitution pattern of the 1,2-dibromoben-

zene. For example, the cross-coupling of 1,2-dibromo-4,5-

dimethoxybenzene (1b) had to be performed at –35 °C to

obtain biaryl 2b in a satisfactory yield (67%; Table 1, en-

tries 4 and 5). In contrast, 1,2-dibromo-4,5-dimethylben-

zene (1c) cleanly gave biphenyl 2c in 57% yield at –78 °C

(Table 1, entry 6).

With 1,2-dibromobenzenes symmetrically functionalized

at the ortho positions, o,oЈ-tetrasubstituted biaryls were

readily obtained (Table 1, entries 8 and 10). Compared with

its meta isomer 1c, which cleanly reacted at –78 °C, the 1,2-

dibromobenzene 1d, which bears methyl groups ortho to the

benzyne functionality, was converted into biaryl 2d in 49%

yield when the aryne cross-coupling was performed at 0 °C.

At a lower temperature, the proportion of the brominated

side-product 3 in the reaction mixture increased (Table 1,

entry 7). This lack of reactivity was certainly due to the

steric repulsion of the neighboring methyl groups that lim-

ited, in favor of the halogen/metal permutation, the attack

of the nucleophilic aryllithium intermediate on the transient

benzyne species. In the case of the 1,2-dibromobenzene 1e

substituted with TMS groups, the highly sterically hindered

biaryl structure 2e was obtained at 25 °C in 77% yield. The

structure was confirmed by single-crystal X-ray analysis

(Figure 4).

Figure 2. Regioselectivity of the addition of aryllithium to arynes.

1,3-Dimethoxybenzene was chosen as a model com-

pound due to its facile metalation with butyllithium in THF

at room temperature thus avoiding the use of nucleophiles,

which might obstruct a clean aryne coupling. We systemati-

cally studied the influence of different reaction conditions

on the outcome of the aryne coupling (electronic effects,

steric hindrance of the substituents, temperature, etc.) that

both control the formation of the aryl–aryl bond and ori-

ent, in the case of dissymmetrical benzyne precursors, the

regioselectivity. In most cases the coupling products, 2-bro-

mobiaryls 2, were easily purified by column chromatog-

raphy or crystallization (Figure 3).

Aryne Cross-Coupling with 3-Functionalized 1,2-

Dibromobenzenes

Next we studied 3-functionalized 1,2-dibromobenzenes

as the benzyne source. The results are depicted in Scheme 1.

When a methyl group is present ortho to the benzyne func-

tionality, a mixture of o,oЈ-tri- and tetrasubstituted ortho-

bromobiaryls (2f-a and 2f-b, respectively) was obtained,

each regioisomer resulting from the attack of 2,6-dimeth-

oxyphenyllithium on each side of the dissymmetrical

benzyne. The less sterically hindered substituted product

(2f-a) was present as the major component according to ¹H

NMR analysis of the reaction mixture (2f-a/2f-b = 84:16)

Figure 3. 1,3-Dimethoxybenzene as the model substrate for eluci-

dating the regioselectivity of the addition of aryllithium to arynes. and was isolated in a yield of 64% by crystallization from

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Aryne Cross-Coupling of Aryllithiums with Dibromobenzenes

Table 1. Aryne cross-coupling reactions with symmetrically substituted 1,2-dibromobenzenes.

1

[a] The proportions of 2, 3, and 1,3-dimethoxybenzene were determined by H NMR analysis of the reaction mixture. [b] Isolated yield

of 2 after crystallization and the solvent given in parentheses.

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343

V. Diemer, M. Begaud, F. R. Leroux, F. Colobert

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Scheme 1.

MeOH. The structure of this major regioisomer 2f-a was

confirmed by single-crystal X-ray analysis (Figure 5). The

regioselectivity of the addition slightly decreased with tem-

perature and is in accord with the literature on the addition

of N-nucleophiles^[20]and heteroaryllithiums.^[21]The arylli-

thium addition to 3-methylbenzyne occurs mainly at the re-

mote meta position relative to the methyl group to minimize

steric repulsions between the incoming nucleophile and the

methyl group (Figure 6, a).

With bulkier substituents than a methyl group, perfect

regioselectivity of the aryne cross-coupling was observed.

Starting from the 1,2-dibromobenzenes 1g–i functionalized

at the ortho position with a TMS group or aryl moieties,

the o,oЈ-trisubstituted biaryl 2g-a as well as the terphenyls

2h-a and 2i-a were the only detected products isolated in

Figure 4. X-ray structure of 2e.^[19]

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Aryne Cross-Coupling of Aryllithiums with Dibromobenzenes

69, 31, and 67% yields, respectively. The structures of 2g-a

and 2i-a were determined by single-crystal X-ray analysis

(see Figures 7 and 8) and indicated that the addition of the

nucleophile occurred exclusively on the sterically less hin-

dered side of the benzyne (Figure 6, a).

Figure 5. X-ray structure of 2f-a.^[19]

Figure 7. X-ray structure of 2g-a.^[19]

Figure 8. X-ray structure of 2i-a.^[19]

This perfect regioselectivity has already been observed

by Hiyama and co-workers in benzodiazepine synthesis.^[22]

Similarly, the only isolated regioisomer resulting from aryl-

lithium addition to 3-phenylbenzyne, obtained as a tran-

sient species from 2,3-dibromobiphenyl (1h), corroborated

the selectivity of the aryne cross-coupling reaction.

In the case of dissymmetrical coupling partners, the re-

gioselectivity of the reaction is highly dependent upon the

relative steric hindrance of the ortho substituents. Owing to

the poor regioselectivity of the aryllithium addition to the

benzyne resulting from 1,2-dibromo-3-methylbenzene (1f)

we decided to introduce a sterically demanding TMS group

at the 6-position. The TMS group has the advantage of be-

ing easily removed at the end of the reaction or to be con-

verted by halo-desilylation into a bromine or iodine atom.

We were therefore satisfied that the reaction with the 1,2-

dibromobenzene 1j furnished with perfect regiocontrol the

coupling product 2j-a in 56% yield. We wish to emphasize

that this o,oЈ-tetrasubstituted biphenyl is obtained in excel-

lent yield without any ligands or transition metals. The sin-

gle-crystal X-ray structure of 2j-a unambiguously shows

Figure 6. Regioselectivity of the aryne coupling reaction.

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V. Diemer, M. Begaud, F. R. Leroux, F. Colobert

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that the C–C bond was created, as expected, ortho to the

methyl group (i.e., on the sterically less hindered side of the

intermediate benzyne) (Figure 6a and Figure 9).

Scheme 2.

Benzyne precursors like 1k bearing a hetero-element such

as a methoxy group in the ortho position afford exclusively

a single regioisomer (2k-a) isolated in 64% yield. Regiocon-

trolled additions to arynes have been reported in some

cases.^{[6e,20b,21,23]}The regioselectivity can be attributed to a

combination of steric and electronic effects. As previously

seen, steric hindrance by the methoxy group favors the ad-

Figure 9. X-ray structure of 2j-a.^[19]

Desilylation of compound 2j-a in THF with TBAF led

to the minor regioisomer 2f-b in a mixture with the fluoro

derivative 4a (47%, 2f-b/4a = 46:54; Scheme 2).

Scheme 3.

Scheme 4.

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Aryne Cross-Coupling of Aryllithiums with Dibromobenzenes

dition of the aryllithium at the meta position relative to the methyl groups at the ortho position of the aryl–aryl bond

substituent. This selectivity is amplified by the stabilization are more shielded than those at meta positions. For exam-

of the resulting 2-biaryllithium intermediate (Figure 6b). ple, the signal of the methyl group was shifted upfield from

Gorecka-Kobylinska and Schlosser recently reported on the 2.48 to 2.04 ppm for biaryls 2j-a and 2f-a substituted at the

stabilization of various substituents at the ortho, meta, or 2- and 3-positions, respectively. Similar results were ob-

para positions relative to lithium. According to their studies tained with the 3,6-dimethylated biaryl 2d [δ(3-CH₃) =

1

the methoxy group stabilizes an adjacent aryllithium by 2.43 ppm; δ(6-CH₃) = 2.01 ppm]. At the same time the H

2.7 kcal/mol.^[24]

NMR signal of the methyl group was detected at δ =

So far the regioselectivity of the aryne coupling has been 1.99 ppm in the case of biaryl 2l-a. On the basis of our

dictated either by steric effects (Figure 6, a) or by a combi- previous observations, this result clearly indicates that the

nation of steric and electronic effects (Figure 6, b). In the coupling occurred only under electronic control at the ortho

following model reaction we were intrigued to see which position of the methyl group (Scheme 3). In spite of the fact

effect, steric or electronic, would dominate in the addition that the attack of the nucleophile is disfavored by the steric

of 2,6-dimethoxyphenyllithium to 2-methoxy-6-methyl- hindrance of the methyl group, the electronic stabilization

benzyne. The reaction had to be conducted at 0 °C. Only of the intermediate 2-biaryllithium induced by the adjacent

one regioisomer (2l-a) was formed (according to GC–MS methoxy group largely directs the coupling process and ex-

analysis). To determine the structure of 2l-a and to eluci- plains the exclusive formation of the biaryl 2l-a (Figure 6,

1

date the regioselectivity of the aryne coupling, H NMR c). Nevertheless, despite having no effect on the regioselec-

spectroscopic data of the methylated compounds 2d, 2f-a, tivity of the aryne coupling, the steric hindrance induced

2j-a, and 2l-a were compared. Owing to their spatial orien- by the methyl group seems to be responsible for the low

tation in the direction of the 2,6-dimethoxyphenyl moiety, yield of the reaction (28%).

Scheme 5.

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V. Diemer, M. Begaud, F. R. Leroux, F. Colobert

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Aryne Cross-Coupling with 4-Functionalized 1,2-

Dibromobenzenes

under similar conditions starting from silane 2p-a afforded

the expected biaryl 2m-a together with the fluoro derivative

4b (54%, 2m-a/4b = 47:53).

When the aryne cross-coupling was performed on 1,2-

dibromobenzenes 1m and 1n functionalized at the 4-posi-

tion with a methyl or methoxy group, mixtures of equal

amounts of the corresponding two regioisomers were ob-

tained. In the case of the 1,2-dibromobenzene 1o substi-

tuted with a phenyl group, NMR analysis indicated a slight

Aryne Cross-Coupling with 3-Halogenated 1,2-

Dibromobenzenes

The aryne cross-coupling reaction performed with 3-

preference for the regioisomer 2o-a (2o-a/2o-b = 60:40). The fluoro-1,2-dibromobenzene (1r) at 0 °C did not lead, as ex-

addition of aryllithium to the meta or para positions rela- pected, to one of the biaryls 2r-a or 2r-b but to the ter-

tive to the benzyne substituent implies neither steric prefer- phenyl 2i-a obtained previously (Scheme 6). This com-

ence nor extra electronic stabilization and therefore gives pound, isolated in 24% yield after crystallization from

both regioisomers (Scheme 4).

EtOAc, resulted from a double addition of 2,6-dimeth-

Once again, to perform the aryne coupling reaction re- oxyphenyllithium to the polyhalogenated aromatic ring. In-

gioselectively we introduced a bulky TMS group on to the creasing the proportion of the aryllithium in the reaction

benzyne precursor (Scheme 5). The silylated 1,2-dibro- mixture did not improve the yield. When the reaction was

mobenzenes 1p and 1q afforded readily and in perfect re- conducted at a lower temperature, –35 °C instead of 0 °C,

gioselectivity the desired biaryls 2p-a and 2q-a in 62 and the starting material was recovered together with 2-bromo-

47% yields, respectively. The aryllithium intermediate adds 1,3-dimethoxybenzene (3) as a result of direct halogen/

to the remote position to avoid steric repulsion with the metal exchange.

TMS group. As a consequence, the methyl and phenyl sub-

The formation of terphenyl 2i-a can be explained by two

stituents in the cross-coupling products 2p-a and 2q-a are consecutive aryne cross-coupling reactions (Figure 10).

now at the meta position of the newly created C–C bond. First, 2,6-dimethoxyphenyllithium is involved in a bromine/

Desilylation of compound 2q-a was performed in THF with lithium permutation with the 1-fluoro- or 1-chloro-2,3-di-

TBAF and afforded after crystallization from methanol re- bromobenzene, the bromine atom adjacent to the fluorine

gioisomer 2o-a in 40% yield. Removal of the TMS group or chlorine atom being replaced. Elimination of lithium

Scheme 6.

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Aryne Cross-Coupling of Aryllithiums with Dibromobenzenes

Figure 10. Terphenyl formation by aryne coupling.

bromide affords the transient aryne species. Nucleophilic progress made in developing synthetic routes to function-

addition of 2,6-dimethoxyphenyllithium affords an aryl- alized 1,2-dibromobenzenes, the aryne cross-coupling reac-

lithium intermediate, which undergoes a further lithium ha- tion has become a powerful alternative to the classic transi-

lide elimination and generates another aryne. The latter tion-metal-catalyzed cross-coupling protocols.

adds another equivalent of 2,6-dimethoxyphenyllithium

and is stabilized by a bromine/lithium permutation with the

remaining starting material affording the terphenyl 2i-a. A

Experimental Section

few cases of successive nucleophilic additions to arynes have

been described in the literature.^{[13a–13c,25]}

General Methods: Starting materials, if commercial, were purchased

and used as such, provided that adequate checks (melting ranges,

refractive indices, and gas chromatography) had confirmed the

Conclusions

claimed purity. When known compounds were prepared according

to literature procedures, pertinent references are given. Air- and

moisture-sensitive materials were stored in Schlenk tubes. They

In this work we studied the regioselectivity of the aryne

cross-coupling reaction by using various dissymmetric

benzynes. These highly reactive intermediates were gener-

ated for the first time starting from functionalized 1,2-di-

bromobenzene precursors, recently accessible through short

and efficient synthetic pathways. o,oЈ-Tri- and -tetrasubsti-

tuted bromobiphenyls were efficiently synthesized by this

transition-metal-free cross-coupling procedure. We have

shown how substituents present at the ortho, meta, or para

positions relative to the benzyne functionality control by

steric and/or electronic effects the addition of the arylli-

thium intermediate. As a consequence, the temperature of

the reaction had to be optimized, especially when sensitive

aryllithium species were used as the coupling partner. We

showed that the introduction of bulky or chelating substitu-

ents at the ortho position of the benzyne directed the ad-

dition of the nucleophile during the coupling reaction. In

this way, the coupling of dissymmetrical 1,2-dihalogenated

benzyne precursors, otherwise lacking regioselectivity, oc-

were protected by and handled under argon, using appropriate

glassware. Tetrahydrofuran was dried by distillation from sodium

after the characteristic blue color of sodium diphenyl ketyl (benzo-

phenone-sodium “radical anion”) had been found to persist. Melt-

ing ranges were determined with a Kofler hot-plate and found to

be reproducible after recrystallization unless stated otherwise (“de-

comp.”). If melting points are missing, it means all attempts to

crystallize the liquid at temperatures down to –75 °C failed. Col-

umn chromatography was carried out on a column packed with

silica-gel 60N (spherical neutral size 63–210 μm). ¹H and ¹H-de-

coupled ¹³C NMR spectra were recorded at 400 or 300 and 101 or

75 MHz, respectively. Chemical shifts are reported in δ units (ppm)

and were measured relative to the signals for residual chloroform (δ

= 7.26 ppm for ¹H NMR and 77.16 ppm for ¹³C NMR). Coupling

constants J are given in Hz. Coupling patterns are abbreviated, for

example, as s (singlet), d (doublet), t (triplet), q (quartet), quint.

(quintet), td (triplet of doublets), m (multiplet), app. s (apparent

singlet), and br. (broad).

The 1,2-dibromobenzene derivatives 1a–c,m are commercially avail-

curred with complete regiocontrol. Considering the recent able and the 1,2-dibromobenzenes 1d–i,k–l,o–s were synthesized ac-

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V. Diemer, M. Begaud, F. R. Leroux, F. Colobert

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cording to methods developed in our laboratory or described in

the literature.^[17]

(m, 2 H, Ar-H), 7.31–7.38 (m, 2 H, Ar-H), 7.66 (br. d, J = 8.1 Hz,

1 H, Ar-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 56.1 (2 CH₃),

104.2 (2 CH), 119.0 (C), 125.4 (C), 127.0 (CH), 128.7 (CH), 129.6

(CH), 132.4 (CH), 132.4 (CH), 136.2 (C), 157.8 (2 C) ppm.

(2,3-Dibromo-4-methylphenyl)trimethylsilane (1j): Lithium tet-

ramethylpiperidide (LTMP; 20.0 mmol) was added dropwise to

TMSCl (2.54 mL, 20.0 mmol) and 1,2-dibromo-3-methylbenzene

(2.50 g, 10.0 mmol) in anhydrous THF (10 mL) under Ar at –78 °C.

LTMP was prepared in anhydrous THF (10 mL) at 0 °C by depro-

tonation of tetramethylpiperidine (3.37 mL, 20.0 mmol) with BuLi

(20.0 mmol) in hexane (12.5 mL). The mixture was stirred at –78 °C

for 2 h and then hydrolyzed with methanol (20 mL) at –78 °C and

with water (20 mL) at 25 °C. The organic layer obtained after ad-

dition of Et₂O (200 mL) was successively washed with 1 m aqueous

HCl (2ϫ100 mL) and water (1ϫ100 mL) and dried with Na₂SO₄.

The solvents were evaporated under reduced pressure and the silane

1j contained in the crude was purified by column chromatography

(cyclohexane). The isolated product (2.76 g) was used in the next

step in spite of the presence of impurities (10%). ¹H NMR

(300 MHz, CDCl₃): δ = 0.38 [s, 9 H, Si(CH₃)₃], 2.47 (s, 3 H, Ar-

CH₃), 7.14 (d, J = 7.5 Hz, 1 H, Ar-H), 7.25 (d, J = 7.5 Hz, 1 H,

Ar-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –0.2 (3 CH₃), 25.5

(CH₃), 128.9 (C), 129.0 (CH), 132.8 (C), 134.3 (CH), 141.7 (C),

141.8 (C) ppm.

2-Bromo-4,5,2Ј,6Ј-tetramethoxybiphenyl

(2b):

Butyllithium

(5.00 mmol) in hexane (3.12 mL) was added dropwise to a solution

of 1,3-dimethoxybenzene (0.69 g, 5.00 mmol) in anhydrous THF

(12.5 mL) under Ar at 0 °C. The mixture was stirred at 25 °C for

5 h and was then cooled to –35 °C. A solution of the 1,2-dibro-

mobenzene 2b (6.00 mmol, 1.77 g) in anhydrous THF was added

dropwise. The mixture was stirred at –35 °C for 3 h and then

warmed to 25 °C overnight. Water (150 mL) was added and the

mixture was extracted with Et₂O (3ϫ100 mL). The combined or-

ganic layers were dried with Na₂SO₄and evaporated under reduced

pressure. Purification of the crude product by column chromatog-

raphy (cyclohexane/EtOAc, 8:2) followed by crystallization from

MeOH afforded the biaryl 2b (1.20 g, 67%) as a colorless solid.

The spectroscopic data are in agreement with the literature.^{[8a] 1}

H

NMR (300 MHz, CDCl₃): δ = 3.76 (s, 6 H, 2 OCH₃), 3.83 (s, 3 H,

OCH₃), 3.90 (s, 3 H, OCH₃), 6.65 (d, J = 8.4 Hz, 2 H, Ar-H), 6.74

(s, 1 H, Ar-H), 7.13 (s, 1 H, Ar-H), 7.33 (t, J = 8.4 Hz, 1 H, Ar-

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 56.1 (CH₃), 56.1 (CH₃),

56.2 (2 CH₃), 104.3 (2 CH), 115.0 (CH), 115.3 (C), 115.3 (CH),

119.0 (C), 128.0 (C), 129.5 (CH), 148.2 (C), 148.7 (C), 158.0 (2

C) ppm.

1,2-Dibromo-4-methoxybenzene (1n): A solution of NaNO₂(3.20 g,

46.4 mmol) in water (7.00 mL) was added dropwise to a suspension

of 3,4-dibromoaniline (10.0 g, 40.0 mmol) in aqueous H₂SO₄(pre-

pared from 20.0 mL water and 8.00 mL concentrated H₂SO₄) at

0 °C. After 20 min at 0 °C, urea (0.32 g) was added and the reaction

mixture was poured portionwise into a mixture of water (10.0 mL),

Na₂SO₄(15.0 g), and concentrated H₂SO₄(20.0 mL) heated at

120 °C. The reaction mixture was heated at 120 °C for 2 h and di-

luted, at room temperature, with water (500 mL). The aqueous

layer was then extracted with Et₂O (3ϫ300 mL) and the combined

organic layers were dried with Na₂SO₄. After removal of the sol-

vent under reduced pressure, the residue that contained 3,4-dibro-

mophenol (¹H NMR spectrum was in agreement with the litera-

ture)^[26]was dissolved in acetone (100 mL). MeI (3.00 mL,

48.0 mmol) and K₂CO₃(6.62 g, 48.0 mmol) were successively

added and the mixture was heated at reflux for 5 h. After evapora-

tion of acetone under reduced pressure, the residue was dissolved

in Et₂O (400 mL) and the obtained organic layer was successively

washed with 1 m aqueous NaOH (200 mL) and water (2ϫ200 mL),

dried with Na₂SO₄, and evaporated under reduced pressure. Distil-

lation of the crude (99–105 °C, 1 mbar) furnished anisole 1n

(3.55 g) as an oil. Purification of the residue by column chromatog-

raphy (cyclohexane) gave an additional fraction of 1n (0.82 g).

Yield: 41%. The spectroscopic data are in agreement with the lit-

erature.^{[27] 1}H NMR (300 MHz, CDCl₃): δ = 3.78 (s, 3 H, OCH₃),

6.73 (dd, J = 2.9, 8.8 Hz, 1 H, Ar-H), 7.17 (d, J = 2.9 Hz, 1 H, Ar-

H), 7.48 (d, J = 8.8 Hz, 1 H, Ar-H) ppm.

2-Bromo-2Ј,6Ј-dimethoxy-4,5-dimethylbiphenyl (2c): Butyllithium

(5.00 mmol) in hexane (3.12 mL) was added dropwise to a solution

of 1,3-dimethoxybenzene (0.69 g, 5.00 mmol) in anhydrous THF

(12.5 mL) under Ar at 0 °C. The mixture was stirred at 25 °C for

5 h and was then cooled to –78 °C. A solution of the 1,2-dibro-

mobenzene 1c (6.00 mmol, 1.58 g) in anhydrous THF was added

dropwise. The mixture was stirred at –78 °C for 3 h and then

warmed to 25 °C overnight. Water (150 mL) was added and the

mixture was extracted with Et₂O (3ϫ100 mL). The combined or-

ganic layers were dried with Na₂SO₄and evaporated under reduced

pressure. Crystallization from MeOH afforded the biaryl 2c (0.91 g,

57%) as a colorless solid; m.p. 138–139 °C. ¹H NMR (300 MHz,

CDCl₃): δ = 2.24 (s, 3 H, Ar-CH₃), 2.28 (s, 3 H, Ar-CH₃), 3.76 (s,

6 H, 2 OCH₃), 6.66 (d, J = 8.3 Hz, 2 H, Ar-H), 7.02 (s, 1 H, Ar-

H), 7.33 (t, J = 8.3 Hz, 1 H, Ar-H), 7.45 (s, 1 H, Ar-H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 19.5 (CH₃), 19.5 (CH₃), 56.2 (2 CH₃),

104.2 (2 CH), 119.0 (C), 121.9 (C), 129.3 (CH), 133.1 (C), 133.2

(CH), 133.3 (CH), 135.5 (C), 137.5 (C), 157.9 (2 C) ppm.

C₁₆H₁₇BrO₂(321.21): C 59.83, H 5.33; found C 59.87, H 5.24.

2-Bromo-2Ј,6Ј-dimethoxy-3,6-dimethylbiphenyl (2d): Butyllithium

(1.65 mmol) in hexane (1.03 mL) was added dropwise to a solution

of 1,3-dimethoxybenzene (0.23 g, 1.65 mmol) in anhydrous THF

(4.00 mL) under Ar at 0 °C. The mixture was stirred at 25 °C for

5 h and was then cooled to 0 °C. A solution of the 1,2-dibromoben-

zene 1d (1.98 mmol, 0.52 g) in anhydrous THF was added drop-

wise. The mixture was stirred at 0 °C for 3 h and then warmed to

25 °C overnight. Water (60 mL) was added and the mixture was

2Ј-Bromo-2,6-dimethoxybiphenyl (2a): Butyllithium (5.00 mmol) in

hexane (3.12 mL) was added dropwise to a solution of 1,3-dime-

thoxybenzene (0.69 g, 5.00 mmol) in anhydrous THF (12.5 mL) un-

der Ar at 0 °C. The mixture was stirred at 25 °C for 5 h and was extracted with Et₂O (3ϫ50 mL). The combined organic layers were

then cooled to 0 °C. 1,2-Dibromobenzene (1a; 6.00 mmol, 0.72 mL)

was added dropwise. The mixture was stirred at 0 °C for 3 h and

then warmed to 25 °C overnight. Water (150 mL) was added and

the mixture was extracted with Et₂O (3ϫ100 mL). The combined

organic layers were dried with Na₂SO₄and evaporated under re-

duced pressure. Crystallization from MeOH afforded the biaryl 2a

(0.86 g, 59%) as a colorless solid. The spectroscopic data are in

agreement with the literature.^{[14] 1}H NMR (300 MHz, CDCl₃): δ =

3.74 (s, 6 H, 2 OCH₃), 6.65 (d, J = 8.4 Hz, 2 H, Ar-H), 7.17–7.25

dried with Na₂SO₄and evaporated under reduced pressure. Purifi-

cation of the crude product by column chromatography (cyclohex-

ane/CH₂Cl₂, 75:25) followed by crystallization from MeOH af-

forded the biaryl 2d (0.26 g, 49%) as a colorless solid; m.p. 113–

1

114 °C. H NMR (300 MHz, CDCl₃): δ = 2.01 (s, 3 H, Ar-CH₃),

2.43 (s, 3 H, Ar-CH₃), 3.73 (s, 6 H, 2 OCH₃), 6.66 (d, J = 8.3 Hz,

2 H, Ar-H), 7.12 (br. s, 2 H, Ar-H), 7.35 (t, J = 8.3 Hz, 1 H, Ar-

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 20.6 (CH₃), 24.0 (CH₃),

56.2 (2 CH₃), 104.3 (2 CH), 119.1 (C), 127.9 (C), 128.2 (CH), 129.3

350

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Eur. J. Org. Chem. 2011, 341–354

Aryne Cross-Coupling of Aryllithiums with Dibromobenzenes

(CH), 129.5 (CH), 135.4 (C), 136.1 (C), 136.8 (C), 157.5 (2 C) ppm.

C₁₆H₁₇BrO₂(321.21): C 59.83, H 5.33; found C 59.51, H 5.60.

a solution of 1,3-dimethoxybenzene (0.55 g, 4.00 mmol) in anhy-

drous THF (10.0 mL) under Ar at 0 °C. The mixture was stirred at

25 °C for 5 h and was then cooled to –35 °C. A solution of the

1,2-dibromobenzene 1g (4.80 mmol, 1.48 g) in anhydrous THF was

added dropwise. The mixture was stirred at –35 °C for 3 h and then

warmed to 25 °C overnight. Water (120 mL) was added and the

mixture was extracted with Et₂O (3ϫ80 mL). The combined or-

ganic layers were dried with Na₂SO₄and evaporated under reduced

pressure. Purification of the crude product by column chromatog-

raphy (cyclohexane/CH₂Cl₂, 80:20) afforded the biaryl 2g-a (1.01 g,

69%) as a colorless solid; m.p. 124 °C. ¹H NMR (300 MHz,

CDCl₃): δ = 0.42 [s, 9 H, Si(CH₃)₃], 3.73 (s, 6 H, 2 OCH₃), 6.65 (d,

J = 8.3 Hz, 2 H, Ar-H), 7.20 (dd, J = 1.9, 7.4 Hz, 1 H, Ar-H), 7.33

(t, J = 8.3 Hz, 1 H, Ar-H), 7.34 (t, J = 7.4 Hz, 1 H, Ar-H), 7.42

(dd, J = 1.9, 7.4 Hz, 1 H, Ar-H) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 0.0 (3 CH₃), 56.2 (2 CH₃), 104.3 (2 CH), 120.1 (C), 126.3 (CH),

129.4 (CH), 133.2 (CH), 133.3 (C), 135.1 (CH), 136.5 (C), 141.7

(C), 157.8 (2 C) ppm. C₁₇H₂₁BrO₂Si (365.34): C 55.89, H 5.79;

found C 55.63, H 6.07.

2-Bromo-2Ј,6Ј-dimethoxy-3,6-bis(trimethylsilyl)biphenyl (2e): Butyl-

lithium (5.00 mmol) in hexane (3.12 mL) was added dropwise to a

solution of 1,3-dimethoxybenzene (0.69 g, 5.00 mmol) in anhydrous

THF (12.5 mL) under Ar at 0 °C. The mixture was stirred at 25 °C

for 5 h and a solution of the 1,2-dibromobenzene 1e (6.00 mmol,

2.28 g) in anhydrous THF was added dropwise. The mixture was

stirred at 25 °C for 18 h, hydrolyzed with water (150 mL), and ex-

tracted with Et₂O (3ϫ100 mL). The combined organic layers were

dried with Na₂SO₄and evaporated under reduced pressure. Purifi-

cation of the crude product by column chromatography (cyclohex-

ane/CH₂Cl₂, 85:15) afforded the biaryl 2e (1.69 g, 77%) as a color-

less solid; m.p. 118–119 °C. ¹H NMR (300 MHz, CDCl₃): δ = –0.06

[s, 9 H, Si(CH₃)₃], 0.41 [s, 9 H, Si(CH₃)₃], 3.70 (s, 6 H, 2 OCH₃),

6.60 (d, J = 8.3 Hz, 2 H, Ar-H), 7.35 (t, J = 8.3 Hz, 1 H, Ar-H),

7.43 (d, J = 7.3 Hz, 1 H, Ar-H), 7.56 (d, J = 7.3 Hz, 1 H, Ar-

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –0.5 (3 CH₃), –0.1 (3

CH₃), 55.6 (2 CH₃), 103.6 (2 CH), 120.6 (C), 129.6 (CH), 132.7

(CH), 134.6 (CH), 134.8 (C), 141.6 (C), 142.5 (C), 144.0 (C), 158.2 2Ј-Bromo-2,6-dimethoxy-1,1Ј:3Ј,1ЈЈ-terphenyl (2h-a): Butyllithium

(2 C) ppm. C₂₀H₂₉BrO₂Si₂(437.52): C 54.90, H 6.68; found C (5.00 mmol) in hexane (3.12 mL) was added dropwise to a solution

54.53, H 7.08.

of 1,3-dimethoxybenzene (0.69 g, 5.00 mmol) in anhydrous THF

(12.5 mL) under Ar at 0 °C. The mixture was stirred at 25 °C for

5 h and was then cooled to –35 °C. A solution of the 1,2-dibro-

mobenzene 1h (6.00 mmol, 1.87 g) in anhydrous THF was added

dropwise. The mixture was stirred at –35 °C for 3 h and then

warmed to 25 °C overnight. Water (150 mL) was added and the

mixture was extracted with Et₂O (3ϫ100 mL). The combined or-

ganic layers were dried with Na₂SO₄and evaporated under reduced

pressure. Purification of the crude product by column chromatog-

raphy (cyclohexane/CH₂Cl₂, 75:25) followed by crystallization from

MeOH at –20 °C afforded the biaryl 2h-a (0.58 g, 31%) as a color-

less solid; m.p. 119–120 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.77

(s, 6 H, 2 OCH₃), 6.67 (d, J = 8.4 Hz, 2 H, Ar-H), 7.21 (dd, J =

1.8, 7.5 Hz, 1 H, Ar-H), 7.29 (dd, J = 1.8, 7.6 Hz, 1 H, Ar-H),

7.33–7.51 (m, 7 H, Ar-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

56.2 (2 CH₃), 104.3 (2 CH), 119.9 (C), 125.6 (C), 126.8 (CH), 127.4

(CH), 127.9 (2 CH), 129.5 (CH), 129.8 (2 CH), 130.0 (CH), 131.1

(CH), 137.3 (C), 142.4 (C), 143.2 (C), 157.8 (2 C) ppm. C₂₀H₁₇BrO₂

(369.25): C 65.05, H 4.64, found C 65.14, H 4.73.

2-Bromo-2Ј,6Ј-dimethoxy-3-methylbiphenyl (2f-a): Butyllithium

(1.00 mmol) in hexane (0.13 mL) was added dropwise to a solution

of 1,3-dimethoxybenzene (0.14 g, 1.00 mmol) in anhydrous THF

(2.5 mL) under Ar at 0 °C. The mixture was stirred at 25 °C for 5 h

and was then cooled to –78 °C. A solution of the 1,2-dibromoben-

zene 1f (1.20 mmol, 0.30 g) in anhydrous THF was added dropwise.

The mixture was stirred at –78 °C for 3 h and was warmed to 25 °C

overnight. Water (60 mL) was added and the mixture was extracted

with Et₂O (3ϫ50 mL). The combined organic layers were dried

with Na₂SO₄and evaporated under reduced pressure. Regioisomers

2f-a and 2f-b (2f-a/2f-b, 84:16 according to NMR analysis) con-

tained in the crude product were isolated as a mixture by

chromatography (cyclohexane/CH₂Cl₂, 8:2). Crystallization from

MeOH afforded the biaryl 2f-a (0.20 g, 64%) as a colorless solid;

m.p. 123–124 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.48 (s, 3 H,

Ar-CH₃), 3.74 (s, 6 H, 2 OCH₃), 6.66 (d, J = 8.4 Hz, 2 H, Ar-H),

7.05 (dd, J = 2.4, 6.9 Hz, 1 H, Ar-H), 7.19–7.28 (m, 2 H, Ar-H),

7.34 (t, J = 8.4 Hz, 1 H, Ar-H) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 24.2 (CH₃), 56.2 (2 CH₃), 104.2 (2 CH), 120.0 (C), 126.7 (CH), 2Ј-Bromo-2,6,2ЈЈ,6ЈЈ-tetramethoxy-[1,1Ј;3Ј,1ЈЈ]terphenyl (2i-a)

127.8 (C), 129.3 (CH), 129.6 (CH), 129.7 (CH), 136.7 (C), 138.3

Synthesis of 2i-a by Direct Aryne Cross-Coupling: Butyllithium

(C), 157.8 (2 C) ppm. C₁₅H₁₅BrO₂(307.18): C 58.65, H 4.92; found

(2 mmol) in hexane (1.25 mL) was added dropwise to a solution

C 58.42, H 4.91.

of 1,3-dimethoxybenzene (0.28 g, 2.00 mmol) in anhydrous THF

2Ј-Bromo-2,6-dimethoxy-6Ј-methylbiphenyl (2f-b): A solution of tet-

rabutylammonium fluoride (4.50 mmol) in THF (4.50 mL) was

added to silane 2j-a (1.50 mmol, 568 mg) in anhydrous THF

(15.0 mL) under Ar at 25 °C. The mixture was stirred at 25 °C for

16 h, hydrolyzed with water (100 mL), and diluted with Et₂O

(100 mL). The organic layer was separated, washed with water

(2ϫ100 mL), dried with Na₂SO₄, and evaporated under reduced

pressure. Purification of the crude by column chromatography (cy-

clohexane/CH₂Cl₂, 8:2) afforded a mixture (200 mg, 47%) of bi-

aryls 2f-b and 4a (2f-b/4a, 46:54). The ¹H NMR spectrum of biaryl

2f-b was determined by comparison of the spectroscopic data of

mixtures 2f-b/4a and 2f-a/2f-b. ¹H NMR (300 MHz, CDCl₃): δ =

2.06 (s, 3 H, Ar-CH₃), 3.74 (s, 6 H, 2 OCH₃), 6.66 (d, J = 8.4 Hz,

2 H, Ar-H), 7.10 (t, J = 7.7 Hz, 1 H, Ar-H), 7.20–7.22 (m, 1 H,

Ar-H), 7.35 (t, J = 8.4 Hz, 1 H, Ar-H), 7.49 (d, J = 7.9 Hz, 1 H,

Ar-H) ppm.

(5.00 mL) under Ar at 0 °C. The mixture was stirred at 25 °C for

5 h and was then cooled to –35 °C. A solution of the 1,2-dibro-

mobenzene (1i) (2.40 mmol, 0.89 g) in anhydrous THF was added

dropwise. The mixture was stirred at –35 °C for 3 h and then

warmed to 25 °C overnight. Water (60 mL) was added and the mix-

ture was extracted with Et₂O (3ϫ40 mL). The combined organic

layers were dried with Na₂SO₄and evaporated under reduced pres-

sure. Purification of the crude product by column chromatography

(cyclohexane/CH₂Cl₂, 6:4) afforded the biaryl 2i-a (0.57 g, 67%) as

a colorless solid.

Synthesis of 2i-a by Consecutive Aryne Cross-Coupling: Butyllith-

ium (5.00 mmol) in hexane (3.12 mL) was added dropwise to a

solution of 1,3-dimethoxybenzene (0.69 g, 5.00 mmol) in anhydrous

THF (12.5 mL) under Ar at 0 °C. The mixture was stirred at 25 °C

for 5 h and then cooled to 0 °C. A solution of the 1,2-dibromoben-

zene (1r) (6.00 mmol, 1.52 g) in anhydrous THF was added drop-

wise. The mixture was stirred at 0 °C for 3 h and then warmed to

25 °C overnight. Water (150 mL) was added and the mixture was

(2-Bromo-2Ј,6Ј-dimethoxybiphenyl-3-yl)trimethylsilane (2g-a): Bu-

tyllithium (4.00 mmol) in hexane (2.50 mL) was added dropwise to

Eur. J. Org. Chem. 2011, 341–354

www.eurjoc.org

351

V. Diemer, M. Begaud, F. R. Leroux, F. Colobert

FULL PAPER

extracted with Et₂O (3ϫ100 mL). The combined organic layers

were dried with Na₂SO₄and evaporated under reduced pressure.

Crystallization from EtOAc afforded the biaryl 2i-a (0.25 g, 24%)

as a colorless solid.

ers were dried with Na₂SO₄and evaporated under reduced pres-

sure. Purification of the crude by column chromatography (cyclo-

hexane/CH₂Cl₂, 6:4) gave 2l-a (0.25 g, 28%) as a viscous oil.

Crystallization from MeOH afforded colorless needles. ¹H NMR

(CDCl₃): δ = 1.99 (s, 3 H, CH₃), 3.72 (s, 6 H, 2 OCH₃), 3.90 (s, 3

H, OCH₃), 6.67 (d, J = 8.4 Hz, 2 H, Ar-H), 6.83 (d, J = 8.4 Hz, 1

H, Ar-H), 7.18 (d, J = 8.4 Hz, 1 H, Ar-H), 7.36 (t, J = 8.4 Hz, 1

H, Ar-H) ppm. ¹³C NMR (CDCl₃): δ = 19.9 (CH₃), 56.0 (2 CH₃),

56.2 (CH₃), 104.2 (2 CH), 110.5 (CH), 114.7 (C), 118.3 (C), 128.6

(CH), 129.3 (CH), 131.1 (C), 137.3 (C), 154.0 (C), 157.3 (2 C) ppm.

MS (EI): m/z (%) = 336.0 (9) [M]⁺, 322.0 (23) [M – Me]⁺, 258.1 (6)

[M – Br]⁺, 243.1 (43) [M – Me – Br]⁺, 228 (100) [M – Br –

OMe]⁺, 213.1 (16) [M – Me – Br – OMe]⁺. C₁₆H₁₇BrO₃(337.21):

C 56.99, H 5.08; found C 56.84, H 5.13.

1

2i-a: M.p. 243–245 °C. H NMR (300 MHz, CDCl₃): δ = 3.75 (s,

12 H, 4 OCH₃), 6.65 (d, J = 8.3 Hz, 4 H, Ar-H), 7.19 (d, J =

7.6 Hz, 2 H, Ar-H), 7.32 (t, J = 8.3 Hz, 2 H, Ar-H), 7.36–7.41 (m,

1 H, Ar-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 56.3 (4 CH₃),

104.5 (4 CH), 120.4 (CH), 126.5 (2 C), 128.1 (C), 129.2 (2 CH),

130.8 (2 CH), 136.4 (2 C), 157.9 (4 C) ppm. C₂₂H₂₁BrO₄(429.30):

C 61.55, H 4.93; found C 61.23, H 4.89.

(2-Bromo-2Ј,6Ј-dimethoxy-6-methylbiphenyl-3-yl)trimethylsilane (2j-

a): Butyllithium (8.00 mmol) in hexane (5.00 mL) was added drop-

wise to a solution of 1,3-dimethoxybenzene (1.10 g, 8.00 mmol) in

anhydrous THF (20.0 mL) under Ar at 0 °C. The mixture was

stirred at 25 °C for 5 h and was then cooled to –35 °C. A solution

of the 1,2-dibromobenzene 1j (3.09 g, 9.60 mmol) in anhydrous

THF was added dropwise. The mixture was stirred at –35 °C for

3 h and then warmed to 25 °C overnight. Water (300 mL) was

added and the mixture was extracted with Et₂O (3ϫ200 mL). The

combined organic layers were dried with Na₂SO₄and evaporated

under reduced pressure. Crystallization from MeOH afforded the

biaryl 2j-a (1.50 g) as a colorless solid. Column chromatography

(cyclohexane/CH₂Cl₂, 8:2) of the mother liquors followed by

crystallization from MeOH furnished an additional portion of 2j-

a (0.20 g). Yield: 56%; m.p. 120–121 °C. ¹H NMR (300 MHz,

CDCl₃): δ = 0.40 [s, 9 H, Si(CH₃)₃], 2.04 (s, 3 H, Ar-CH₃), 3.74 (s,

6 H, 2 OCH₃), 6.66 (d, J = 8.4 Hz, 2 H, Ar-H), 7.20 (d, J = 7.5 Hz,

1 H, Ar-H), 7.34 (d, J = 7.5 Hz, 1 H, Ar-H), 7.35 (t, J = 8.4 Hz, 1

H, Ar-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 0.00 (3 CH₃),

21.0 (CH₃), 56.2 (2 CH₃), 104.4 (2 CH), 119.1 (C), 127.9 (CH),

129.4 (CH), 133.8 (C), 135.1 (CH), 136.3 (C), 138.4 (C), 140.9 (C),

157.6 (2 C) ppm. C₁₈H₂₃BrO₂Si (379.36): C 56.99, H 6.11; found

C 56.76, H 6.20.

2-Bromo-2Ј,6Ј-dimethoxy-5-methylbiphenyl (2m-a)

Synthesis of 2m-a by Aryne Cross-Coupling Reaction: Butyllithium

(5.00 mmol) in hexane (3.12 mL) was added dropwise to a solution

of 1,3-dimethoxybenzene (0.69 g, 5.00 mmol) in anhydrous THF

(12.5 mL) under Ar at 0 °C. The mixture was stirred at 25 °C for

5 h and was then cooled to –35 °C. A solution of the 1,2-dibro-

mobenzene 1m (1.50 g, 6.00 mmol) in anhydrous THF was added

dropwise. The mixture was stirred at –35 °C for 3 h and then

warmed to 25 °C overnight. Water (150 mL) was added and the

mixture was extracted with Et₂O (3ϫ100 mL). The combined or-

ganic layers were dried with Na₂SO₄and evaporated under reduced

pressure. Purification of the crude product by column chromatog-

raphy (cyclohexane/CH₂Cl₂, 70:30) afforded a mixture (1.35 g,

88%) of biaryls 2m-a and 2m-b (2m-a/2m-b, 50:50).

Synthesis of 2m-a by Desilylation of Biaryl 2p-a: A solution of tetra-

butylammonium fluoride (3.00 mmol) in anhydrous THF

(3.00 mL) was added to silane 2p-a (0.38 g, 1.00 mmol) in THF

(10 mL) under Ar at 25 °C. The mixture was stirred at 25 °C for

16 h, hydrolyzed with water (100 mL), and extracted with Et₂O

(3ϫ100 mL). The combined organic layers were dried with

Na₂SO₄and evaporated under reduced pressure. Purification of the

crude by column chromatography (cyclohexane/CH₂Cl₂, 80:20) af-

forded a mixture (150 mg, 54%) of biaryls 2m-a and 4b (2m-a/4b,

47:53).

2m-a: The ¹H NMR spectrum of biaryl 2m-a was determined by

comparison of the spectroscopic data of mixtures of 2m-a/4b and

2m-a/2m-b. ¹H NMR (300 MHz, CDCl₃): δ = 2.33 (s, 3 H, Ar-

CH₃), 3.74 (s, 6 H, 2 OCH₃), 6.65 (d, J = 8.3 Hz, 2 H, Ar-H), 6.99–

7.04 (m, 2 H, Ar-H), 7.33 (t, J = 8.3 Hz, 1 H, Ar-H), 7.53 (d, J =

8.1 Hz, 1 H, Ar-H) ppm.

2-Bromo-3,2Ј,6Ј-trimethoxybiphenyl

(2k-a):

Butyllithium

(5.00 mmol) in hexane (3.12 mL) was added dropwise to a solution

of 1,3-dimethoxybenzene (0.69 g, 5.00 mmol) in anhydrous THF

(12.5 mL) under Ar at 0 °C. The mixture was stirred at 25 °C for

5 h and was then cooled to –35 °C. A solution of the 1,2-dibro-

mobenzene 1k (1.60 g, 6.00 mmol) in anhydrous THF was added

dropwise. The mixture was stirred at –35 °C for 3 h and then

warmed to 25 °C overnight. Water (150 mL) was added and the

mixture was extracted with Et₂O (3ϫ100 mL). The combined or-

ganic layers were dried with Na₂SO₄and evaporated under reduced

pressure. Purification of the crude by column chromatography (cy-

clohexane/CH₂Cl₂, 6:4) gave 2k-a (1.03 g, 64%) as a colorless solid;

4Ј-Bromo-2ЈЈ,6ЈЈ-dimethoxy-1,1Ј:3Ј,1ЈЈ-terphenyl (2o-a): A solution

of tetrabutylammonium fluoride (4.50 mmol) in THF (4.50 mL)

was added to silane 2q-a (1.50 mmol, 0.66 g) in anhydrous THF

(15.0 mL) under Ar at 25 °C. The mixture was stirred at 25 °C for

16 h, hydrolyzed with water (100 mL), and diluted with Et₂O

(100 mL). The organic layer was separated, washed with water

(2ϫ100 mL), dried with Na₂SO₄, and evaporated under reduced

pressure. Purification of the crude by column chromatography (cy-

clohexane/CH₂Cl₂, 8:2) followed by crystallization from MeOH at

–20 °C afforded the biaryl 2o-a (0.22 g, 40%) as a colorless solid;

1

m.p. 127–129 °C. H NMR (300 MHz, CDCl₃): δ = 3.73 (s, 6 H, 2

OCH₃), 3.93 (s, 3 H, OCH₃), 6.65 (d, J = 8.4 Hz, 2 H, Ar-H), 6.85–

6.90 (m, 2 H, Ar-H), 7.29–7.36 (m, 2 H, Ar-H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 56.2 (2 CH₃), 56.4 (CH₃), 104.3 (2 CH),

110.5 (CH), 114.8 (C), 119.2 (C), 124.3 (CH), 127.6 (CH), 129.5

(CH), 138.1 (C), 156.2 (C), 157.8 (2 C) ppm. C₁₅H₁₅BrO₃(323.18):

C 55.75, H 4.68; found C 55.41, H 4.45.

2-Bromo-3,2Ј,6Ј-trimethoxy-6-methylbiphenyl (2l-a): Butyllithium

(2.70 mmol) in hexane (1.69 mL) was added dropwise to a solution

of 1,3-dimethoxybenzene (0.37 g, 2.70 mmol) in anhydrous THF

(10.0 mL) under Ar at 0 °C. The mixture was stirred at 25 °C for

5 h and was then cooled to 0 °C. A solution of the 1,2-dibromoben-

zene 1l (0.91 g, 3.24 mmol) in anhydrous THF was added dropwise.

The mixture was stirred at 0 °C for 3 h and then warmed to room

temperature overnight. Water (100 mL) was added and the mixture

was extracted with Et₂O (3ϫ100 mL). The combined organic lay-

1

m.p. 102–105 °C. H NMR (300 MHz, CDCl₃): δ = 3.76 (s, 6 H, 2

OCH₃), 6.67 (d, J = 8.4 Hz, 2 H, Ar-H), 7.30–7.48 (m, 6 H, Ar-

H), 7.58–7.61 (m, 2 H, Ar-H), 7.72 (d, J = 8.2 Hz, 1 H, Ar-H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 56.1 (2 CH₃), 104.2 (2 CH), 118.9

(C), 124.5 (C), 127.2 (2 CH), 127.3 (CH), 127.5 (CH), 128.9 (2

CH), 129.7 (CH), 131.2 (CH), 132.8 (CH), 136.5 (C), 140.0 (C),

140.4 (C), 157.9 (2 C) ppm. C₂₀H₁₇BrO₂(369.25): C 65.05, H 4.64;

found C 65.45, H 4.55.

352

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Eur. J. Org. Chem. 2011, 341–354

Aryne Cross-Coupling of Aryllithiums with Dibromobenzenes

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(2-Bromo-2Ј,6Ј-dimethoxy-5-methylbiphenyl-3-yl)trimethylsilane

(2p-a): Butyllithium (2.00 mmol) in hexane (1.25 mL) was added

dropwise to a solution of 1,3-dimethoxybenzene (0.28 g,

2.00 mmol) in anhydrous THF (5.00 mL) under Ar at 0 °C. The

mixture was stirred at 25 °C for 5 h and was then cooled to –78 °C.

A solution of the 1,2-dibromobenzene 1p (0.77 g, 2.40 mmol) in

anhydrous THF was added dropwise. The mixture was stirred at

–78 °C for 3 h and then warmed to 25 °C overnight. Water (60 mL)

was added and the mixture was extracted with Et₂O (3ϫ40 mL).

The combined organic layers were dried with Na₂SO₄and evapo-

rated under reduced pressure. Purification of the crude product by

column chromatography (cyclohexane/CH₂Cl₂, 75:25) afforded the

[4]

[5]

[6]

1

biaryl 2p-a (0.47 g, 62%) as a colorless solid; m.p. 117–118 °C. H

NMR (300 MHz, CDCl₃): δ = 0.42 [s, 9 H, Si(CH₃)₃], 2.33 (s, 3 H,

Ar-CH₃), 3.74 (s, 6 H, 2 OCH₃), 6.65 (d, J = 8.3 Hz, 2 H, Ar-H),

7.04 (d, J = 1.9 Hz, 1 H, Ar-H), 7.23 (d, J = 1.9 Hz, 1 H, Ar-H),

7.32 (t, J = 8.3 Hz, 1 H, Ar-H) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 0.0 (3 CH₃), 21.1 (CH₃), 56.2 (2 CH₃), 104.3 (2 CH), 120.2 (C),

129.3 (CH), 130.0 (C), 133.9 (CH), 135.7 (C), 136.2 (CH), 136.3

(C), 141.1 (C), 157.9 (2 C) ppm. C₁₈H₂₃BrO₂Si (379.36): C 56.99,

H 6.11; found C 56.81, H 6.27.

[7]

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(4Ј-Bromo-2ЈЈ,6ЈЈ-dimethoxy-1,1Ј:3Ј,1ЈЈ-terphenyl-5Ј-yl)trimethyl-

silane (2q-a): Butyllithium (2.00 mmol) in hexane (1.25 mL) was

added dropwise to a solution of 1,3-dimethoxybenzene (0.28 g,

2.00 mmol) in anhydrous THF (5.00 mL) under Ar at 0 °C. The

mixture was stirred at 25 °C for 5 h and was then cooled to –78 °C.

A solution of the 1,2-dibromobenzene 1q (0.92 g, 2.40 mmol) in

anhydrous THF was added dropwise. The mixture was stirred at

–78 °C for 3 h and then warmed to 25 °C overnight. Water (60 mL)

was added and the mixture was extracted with Et₂O (3ϫ40 mL).

The combined organic layers were dried with Na₂SO₄and evapo-

rated under reduced pressure. Purification of the crude product by

column chromatography (cyclohexane/CH₂Cl₂, 75:25) followed by

crystallization from EtOH afforded the biaryl 2q-a (0.41 g, 47%)

[9]

[10]

[11]

[12]

1

as a colorless solid; m.p. 138–140 °C. H NMR (CDCl₃): δ = 0.47

[s, 9 H, Si(CH₃)₃], 3.75 (s, 6 H, 2 OCH₃), 6.67 (d, J = 8.4 Hz, 2 H,

Ar-H), 7.30–7.44 (m, 5 H, Ar-H), 7.59–7.63 (m, 3 H, Ar-H) ppm.

¹³C NMR (CDCl₃): δ = 0.1 (3 CH₃), 56.2 (2 CH₃), 104.2 (2 CH),

119.9 (C), 127.3 (2 CH), 127.4 (CH), 128.8 (2 CH), 129.5 (CH),

132.0 (CH), 132.5 (C), 133.8 (CH), 136.9 (C), 139.1 (C), 140.8 (C),

141.9 (C), 157.9 (2 C) ppm. C₂₃H₂₅BrO₂Si (441.43): C 62.58, H

5.71; found C 62.47, H 5.63.

[13]

Supporting Information (see also the footnote on the first page of

1

this article): H and ¹³C NMR spectra.

[14]

[15]

Acknowledgments

We are grateful to the Centre National de la Recherche Scientifique

(CNRS), the Ministère de l’Education Nationale et de la Recher-

che, and the Agence Nationale pour la Recherche (ANR program

07-BLAN-0292-01, MetChirPhos) for financial support and a post-

doctoral grant to V. D. The authors thank Patrick Wehrung for his

valuable support in HRMS analysis.

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Received: September 13, 2010

Published Online: December 2, 2010

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Article Doi

Regioselectivity in the aryne cross-coupling of aryllithiums with functionalized 1,2-dibromobenzenes

DOI: 10.1002/ejoc.201001283

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