A practical transition metal-free aryl-aryl coupling method: Arynes as key intermediates

Article abstract of DOI:10.1002/adsc.200700211

Upon treatment of various aryllithium intermediates with 1,2-dibromobenzene or 1-bromo-2-iodobenzene, dissymmetrical ortho,ortho′-di-, tri-and even tetrasubstituted bromo- or iodobiaryls become readily available. The crucial steps in all these reactions were the nucleophilic addition of the organolithium precursor to a transient aryne species released from it by β-elimination of a lithium halide and, stabilization of the resulting 2-biaryllithium intermediate by in situ transfer of bromine or iodine from the starting material. This straightforward transition metal-free access to biaryls allows the preparation of highly valuable halobiaryls on a gram scale in excellent yields. These precursors can be subsequently functionalized by highly regioselective halogen/metal permutations into a vast variety of target molecules. This was demonstrated in the synthesis of several mono- and diphosphine ligands.

Full text of DOI:10.1002/adsc.200700211

UPDATES
DOI: 10.1002/adsc.200700211
A Practical Transition Metal-Free Aryl-Aryl CouplingMethod:
Arynes as Key Intermediates
FrØdØric R. Leroux,a,* Laurence Bonnafoux,a Christophe Heiss,a
FranÅoise Colobert,a and Don Antoine Lanfranchia
a
Laboratoire de stØrØochimie, UniversitØ Louis Pasteur (ECPM), CNRS, 25 rue Becquerel, 67087 Strasbourg Cedex 2,
France
Fax : (+33)-(0)3-9024-2742; e-mail: frederic.leroux@ecpm.u-strasbg.fr
Received: April 26, 2007; Revised: August 13, 2007; Published online: October 4, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Upon treatment of various aryllithium in-
termediates with 1,2-dibromobenzene or 1-bromo-
2-iodobenzene, dissymmetrical ortho,ortho’-di-, tri-
and even tetrasubstituted bromo- or iodobiaryls
become readily available. The crucial steps in all
these reactions were the nucleophilic addition of
the organolithium precursor to a transient aryne
species released from it by b-elimination of a lithi-
um halide and, stabilization of the resulting 2-biar-
yllithium intermediate by in situ transfer of bromine
or iodine from the starting material. This straight-
forward transition metal-free access to biaryls
allows the preparation of highly valuable halobiar-
yls on a gram scale in excellent yields. These precur-
sors can be subsequently functionalized by highly
regioselective halogen/metal permutations into a
vast variety of target molecules. This was demon-
strated in the synthesis of several mono- and di-
phosphine ligands.
tions.[14,15] Moreover, the biphenyl unit belongs to the
six or seven privileged structures[16–20] reputed to be
“safe bets” in pharmaceutical research, as they ascer-
tain versatility and high hit rates. The preparation of
these biaryls often relies on the classical cross-cou-
pling processes such as Suzuki–Miyaura, Negishi,
Kumada–Tamao–Corriu, Stille or Ullmann cou-
pling.[21,22] The limitation of these reactions is often
the preparation of the coupling partners, i.e., the cor-
responding aryl electrophiles and aryl nucleophiles. In
contrast, the functionalization of ortho-bromobiaryls
by halogen/metal interconversion and subsequent re-
action with various electrophiles offers many synthet-
ic advantages.[23–26] However, the synthesis of the
ortho-halobiaryl intermediates is not often straightfor-
ward. In 1957, Gilman[27] and later Lau and co-work-
ers[28] reported the reaction of 1,2-dibromobenzene
with half a molar equivalent of butyllithium in THF
at À788C affording 2,2’-dibromobiphenyl (1,
Scheme 1). These results, together with our previous
work[29] prompted us to investigate the scope and limi-
tations of this highly efficient non-catalyzed carbon-
carbon coupling towards ortho-bromobiaryls having
new and uncommon structural patterns.
À
Keywords: arynes; biaryls; C C coupling; halogen/
metal exchange; phosphines
Introduction
Results and Discussion
Axially chiral, ortho-functionalized biaryls are attract-
ing more and more attention. One reason is the grow- The butyllithium-promoted formation of 2,2’-dibro-
ing number of biologically active natural products mobiphenyl (1) can be explained by three possible
which contain the biaryl motif (for example, vanco- mechanisms. First, an intermediate o-bromophenyl-
mycin, steganone, and michellamine).[1–6] Further- lithium attacks 1,2-dibromobenzene in a kind of SNAr
more, the stereogenic axes provide rigid molecular mechanism (Scheme 1, A). This hypothesis was first
frameworks for highly efficient tools in asymmetric described by Gilman and coworkers[27] in the late
synthesis,[7–11] among them chiral ligands like 1950s. However, such a mechanistic pattern of a stan-
BINAP[12] and MeO-BIPHEP[13] just to mention two dard nucleophilic addition/nucleofugal elimination
of the most prominent ones. The biaryl core is also mode is restricted to heavily strained[30] or acceptor-
commonly encountered in the liquid crystal field, activated[31–33] haloarenes as substrates. Therefore, this
where derivatives have found commercial applica- kind of mechanism can be ruled out.
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Scheme 1. Possible pathways for the butyllithium promoted formation of 2,2’-dibromobiphenyl (1).
Alternatively, the reaction could proceed through a nucleophilic attack at either side to yield product car-
biradical formation and recombination due to the banions.[38]
high propensity of electron-rich aryllithiums to act as
We could experimentally confirm this pathway by
electron donors (Scheme 1, B).[34] Wagner and Mios- treating 1,4-dibromobenzene with half an equivalent
kowski could disqualify the “electron transfer” path- of butyllithium. The SNAr mechanism as well as the
ways by performing the coupling reaction in the ab-
sence of light and in the presence of radical scaveng- (2) as reported by Gilman.[27] However, we were able
ers like TEMPO.[34–36]
to show by careful gas chromatographic analysis that
SRN1 pathway would only afford 4,4’-dibromobiphenyl
An alternative mechanism is based on the interme- 4,4’-dibromobiphenyl (2) (41%) and its 3,4’-isomer 3
diacy of 1,2-didehydrobenzene (1,3-cyclohexadien-5- (21%) were formed concomitantly with bromoben-
yne, benzyne, Scheme 1, C). Here, the crucial steps zene (14%; Scheme 2). These findings are only in
are, first the nucleophilic addition of the organolithi- agreement with a metallation, elimination, addition
um precursor to the transient aryne species released sequence featuring 4-bromophenyllithium, 2,5-dibro-
from it by b-elimination of a lithium halide and, mophenyllithium, and 4-bromo-1,2-didehydrobenzene
second, stabilization of the resulting 2-biaryllithium as transient entities. In fact, 1,4-dibromobenzene un-
intermediate by in situ transfer of bromine.
dergoes an ortho-metallation with 1-bromo-4-lithio-
It has been shown that the reaction of aryl halides benzene as base affording 1,4-dibromo-2-lithioben-
with strong bases involves the intermediate formation zene and bromobenzene. Subsequent lithium bromide
of arynes.[37] Aryne formation occurs via a two-step elimination leads to 4-bromo-1,2-didehydrobenzene
process. Proton abstraction generates the ortho-halo- which in turn adds 4-bromophenyllithium as a nucleo-
aryl carbanion which subsequently eliminates halide phile at the 3- and 4-positions yielding 4,4’- and 3,4’-
to form the aryne. The aryne can then undergo dibromobiphenyl, respectively.
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UPDATES
Scheme 2. Experimental evidence for an aryne intermediate.
Based on these findings, we decided to investigate
The aryl-aryl coupling can be modified by generat-
the scope and limitations in the synthesis of di-, tri- ing the aryne from a thermally labile 2-haloaryllithi-
and tetrasubstituted biaryls.
um species in the presence of a more stable aryllithi-
um compound which will then act as trapping reagent.
In fact, 2-bromophenyllithium formed by halogen/
metal permutation from 1,2-dibromobenzene is labile
at temperatures above À1258C and does not survive
ortho,ortho’-Disubstituted Biaryls
When 1-bromo-2-iodobenzene is used as the starting under the experimental conditions but instantaneous-
material instead of 1,2-dibromobenzene, iodine trans- ly eliminates lithium bromide releasing benzyne. The
fer takes place after treatment with half a molar latter can then be trapped by the thermally less sensi-
equivalent of butyllithium and 2-bromo-2’-iodobi- tive aryllithium component. Under these reaction
phenyl (4) is obtained in a yield of 81%. This access conditions, a hetero-aryl/aryl coupling between two
can be described as a homo-aryl/aryl coupling be- different aryl units can be achieved (Scheme 3).
tween two identical aryllithium species (Scheme 3).
When a solution of 2-bromoanisole was treated
with two equivalents of tert-butyllithium, the corre-
Scheme 3. Synthesis of ortho,ortho’-disubstituted biaryls by homo- and hetero-aryl/aryl coupling.
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FrØdØric R. Leroux et al.
UPDATES
Scheme 4. Synthesis of ortho,ortho’-trisubstituted biaryls by homo- and hetero-aryl/aryl coupling.
sponding 2-anisyllithium reacts with 1,2-dibromoben- generates the aryllithium intermediate very easily.
zene affording 2-bromo-2’-methoxybiphenyl (5) in However, the latter does not react in a clean way
67% yield. The aryllithium intermediate, if not ob- with released benzyne. Indeed, under the reaction
tained by halogen/metal exchange,[24] can be generat- conditions, diisopropylamine adds as a nucleophile to
ed by metallation[25,39] only if the metallating agent is the in situ generated benzyne, leading to undesired
an organolithium base. Trifluoromethoxybenzene was side-products. Therefore, one has to prepare first the
metallated with sec-butyllithium in THF at À758C fol- corresponding aryl iodide by metallation with an
lowed by the addition of 1,2-dibromobenzene. The bi- amide base like LDA followed by trapping with
phenyl 6 was obtained in a yield of 78%. Analogously iodine. The iodo precursor can then be submitted to
1-chloro-2-fluorobenzene gave the biphenyl 7 (74%) an iodine/lithium exchange in order to generate an ar-
and 3-chlorobenzotrifluoride the corresponding deriv- yllithium intermediate without the presence of
ative 8 in a yield of 60%, respectively (Scheme 3).
amines.
ortho,ortho’-Trisubstituted Biaryls
ortho,ortho’-Tetrasubstituted Biaryls
Next, we decided to investigate if trisubstituted biar- To the best of our knowledge, all methods affording
yls will be accessible by this approach. In fact, 1- ortho,ortho’-tetrasubstituted biaryls are based on tran-
bromo-3-fluoro-2-iodobenzene could be easily con- sition metal catalysis (like the copper-catalyzed
verted by homo-aryl/aryl coupling of the intermediate Ullman coupling) and/or require suitable ligands (like
2-bromo-6-fluorophenyllithium into 2-bromo-3’,6-di- in the palladium-catalyzed Suzuki–Miyaura coupling
fluoro-2’-iodobiphenyl (9; 67%), and 1-bromo-3- reaction). In order to investigate the scope and limita-
chloro-2-iodobenzene into 2-bromo-3’,6-dichloro-2’- tions of the transition metal-free aryne coupling, we
iodobiphenyl, respectively (10; 78%; Scheme 4).
decided to treat 9,10-dibromophenanthrene with half
In contrast, when 2-bromo-6-fluorophenyllithium an equivalent of butyllithium. The desired ortho,or-
was treated with one equivalent of 1,2-dibromoben- tho’-tetrasubstituted biphenyl, 10,10’-dibromo-9,9’-bis-
zene at À758C, 2,2’-dibromo-6-fluorobiphenyl (11) phenanthryl (19), was obtained in a good yield of
was obtained in 79% yield by hetero-aryl/aryl cou- 63% (Scheme 5), underlining the great synthetic
pling. As depicted in Scheme 4, various 2,2’,6-trisub- value of this coupling procedure.
stituted biphenyl derivatives (11–18) could be pre-
pared analogously by this approach.
So far, 1,2-dibromobenzene or 1-bromo-2-iodoben-
zene were used as aryne source and the aryllithium
In all these transformations, a clean formation of part was subsequently modified. Therefore we investi-
the aryllithium intermediate (either by halogen/metal gated if the aryne precursor could also be modified.
exchange or by metallation with an alkyllithium base) When 1,3-dimethoxybenzene was submitted to an
is absolutely crucial. For example, the direct metalla- ortho-metallation and the resulting 2-lithio-1,3-dime-
tion of 1-bromo-3-fluorobenzene with LDA or LTMP thoxybenzene was treated with 1,2-dibromo-4,5-dime-
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A Practical Transition Metal-Free Aryl-Aryl Coupling Method
UPDATES
(Scheme 7). However, the electron-rich biaryl 20 af-
forded the desired monophosphine 25 only in a very
poor yield of 7%. The yield could not be improved
by modification of the organolithium base, the solvent
or reaction time.
All phosphines 21–25 were synthesized starting
from mono- or dibromobiaryl intermediates after hal-
ogen/metal exchange and trapping with the appropri-
ate chlorophosphine during the last step of the syn-
thesis. In most cases, the corresponding mono- or di-
phosphines are obtained in excellent yields.
Scheme 5. Synthesis of an ortho,ortho’-tetrasubstituted biaryl
by homo-aryl/aryl coupling.
thoxybenzene (1,2-dibromoveratrole) as “aryne
source”. In this way, we obtained smoothly in a yield
of 55% the highly electron-rich biphenyl 20 Conclusions
(Scheme 6).
In conclusion, we have developed a simple and inex-
pensive method for the synthesis of dissymmetrically
substituted ortho-bromobiaryl building blocks that are
valuable intermediates toward complex ortho-substi-
Synthesis of Phosphine Ligands
Diphosphines supported on stereogenic atropoisomer- tuted biaryl structures. This methodology employs the
ic biaryl scaffolds like BINAP and MeO-BIPHEP, formation of a thermodynamically stable aryllithium
became very efficient chiral inductors in most stereo- intermediate via halogen/metal exchange or metalla-
selective reactions. Dialkylarylphosphine ligands are tion and its subsequent reaction with 1,2-dibromoben-
highly efficient ligands for the Suzuki–Miyaura cou- zene. Experimental details confirm without any doubt
plings of aryl chlorides. As we could show very re- the transient formation of a high-energy species, a
cently, the use of ortho-bromobiaryls allows the 1,2-didehydrobenzene adding a stabilized aryllithium
straightforward synthesis of biaryl mono- and diphos- derivative. The compounds can be prepared on a
phine ligands in a modular way by means of highly se- gram scale without any difficulties and subsequently
lective halogen/metal exchange reactions.[40,41] Thus, functionalized by means of regioselective halogen/
the synthesis of these ortho-bromobiaryls by means of metal permutations into important target molecules
aryne coupling allows the synthesis of new ligands as as exemplified in the synthesis of mono- and diphos-
shown in Scheme 7.
phine ligands. Other classes of substrates are currently
For example 2,2’-dibromo-6-methoxy-biphenyl (13) under investigation to expand the scope of this syn-
could be readily converted into 2,2’-bis(dicyclohexyl- thetically useful non-catalyzed reaction.
phosphine)-6-methoxybiphenyl (21; 74%) by double
bromine/lithium exchange followed by trapping with
two equivalents of chlorodicyclohexylphosphine. In a
similar way the monophosphines 22 and 23 were ob-
Experimental Section
tained after bromine/lithium exchange and subse-
quent trapping of the biphenylyllithium with chlorodi-
General Remarks
Starting materials, if commercial, were purchased and used
as such, provided that adequate checks (melting ranges, re-
fractive indices, and gas chromatography) had confirmed the
claimed purity. When known compounds had to be prepared
according to literature procedures, pertinent references are
given. Air- and moisture-sensitive materials were stored in
cyclohexylphosphine in a yield of 87% and 81%, re-
spectively. 2,2’-Bis(dicyclohexylphosphino)-6-fluorobi-
phenyl (24) was prepared in 79% yield by consecutive
treatment of 2,2’-dibromo-6-fluorobiphenyl (11) with
butyllithium
and
chlorodicyclohexylphosphine
Scheme 6. Aryne coupling using 1,2-dibromoveratrole as aryne source.
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Scheme 7. Synthesis of C1-symmetric biarylmono- and diphosphines.
Schlenk tubes or Schlenk burettes. They were protected by
and handled under an atmosphere of argon, using appropri-
ate glassware. Diethyl ether and tetrahydrofuran were dried
by distillation from sodium after the characteristic blue
color of sodium diphenyl ketyl (benzophenone-sodium “rad-
ical-anion”) had been found to persist.[42,43] Ethereal or
other organic extracts were dried by washing with brine and
then by storage over sodium sulfate. If no reduced pressure
is specified, boiling ranges (b.p.) refer to ordinary atmos-
phere conditions (725Æ25 Torr). Melting ranges (mp) given
were found to be reproducible after recrystallization, unless
stated otherwise (“dec.”), and were corrected using a cali-
bration curve established with authentic standards. If melt-
ing points are missing, it means all attempts to crystallize
the liquid at temperatures down to À758C failed. The tem-
perature of dry ice/acetone baths is consistently indicated as
À758C and “room temperature” (22–268C) as 258C. Silica
gel (Merck Silica Gel 60, 40–63 mm) was used for column
chromatography. The solid support was suspended in hex-
anes and, when all air bubbles had escaped, was washed into
the column. When the level of the liquid was still 3–5 cm
above the support layer, the dry powder, obtained by ad-
sorption of the crude mixture to some 25 mL of silica and
subsequent evaporation of the solvent, was poured on top of
the column. 1H and (1H decoupled) 13C nuclear magnetic
resonance (NMR) spectra were recorded at 400 or 300 and
101 or 75 MHz, respectively. Chemical shifts are reported in
d units, parts per million (ppm) and were measured relative
to the signals for residual chloroform (7.27 ppm). Coupling
constants J are given in Hz. Coupling patterns are abbreviat-
ed as, for example, s (singlet), d (doublet), t (triplet), q
(quartet), quint (quintet), td (triplet of doublets) and m
(multiplet).
StartingMaterials; 1-Bromo-3-fluoro-2-
iodobenzene[29]
At À758C, butyllithium (0.10 mol) in hexanes (55 mL) and
diisopropylamine (14 mL, 10 g, 0.10 mol) were added suc-
cessively to tetrahydrofuran (0.20 L). After 15 min 3-bromo-
fluorobenzene (11 mL, 18 g, 0.10 mol) was added. The mix-
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A Practical Transition Metal-Free Aryl-Aryl Coupling Method
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ture was kept for 2 h at À758C before a solution of iodine
(25 g, 0.10 mol) in tetrahydrofuran (50 mL) was added.
After addition of a 10% aqueous solution (0.10 L) of
sodium thiosulfate, the mixture was extracted with diethyl
ether (3”0.10 L). The combined organic layers were dried
over sodium sulfate before being evaporated to dryness.
Distillation afforded the pure product; yield: 23.47 g (78%).
1-Bromo-3-chloro-2-iodobenzene:[29] Analogously to 1-
bromo-3-fluoro-2-iodobenzene starting from 1-bromo-3-
chlorobenzene (12 mL, 19 g, 0.10 mol). Upon crystallization
from ethanol, colorless needles were obtained; yield: 27.29 g
(86%).
solution of sec-butyllithium (25 mmol) in cyclohexane
(20 mL) and tetrahydrofuran (30 mL). After 2 h at À758C, a
solution of 1,2-dibromobenzene (3.0 mL, 5.9 g, 25 mmol) in
tetrahydrofuran (5.0 mL) was added as described in the pre-
ceding paragraph. The reaction mixture was washed with
brine (3”20 mL) and extracted with diethyl ether (3”
20 mL). Column chromatography on silica gel (100 mL)
using cyclohexane as eluent afforded a colorless oil; yield:
6.18 g (78%).
2-Fluoro-3-chloro-2’-bromobiphenyl (7): Prepared analo-
gously to biphenyl 6 starting from 1-chloro-2-fluorobenzene
(3.3 g, 25 mmol) affording a colorless oil; yield: 5.28 g
(74%).
1,3-Dibromo-2-iodobenzene:[29,40,41] Analogously to 1-
bromo-3-fluoro-2-iodobenzene starting from 1,3-dibromo-
benzene (0.12 L, 0.24 kg, 1.0 mol). Upon crystallization from
ethanol (1.0 L), colorless platelets were obtained; yield:
0.33 kg (91%).
2-Chloro-6-trifluoromethyl-2’-bromobiphenyl (8): Pre-
pared analogously as biphenyl 6 starting from 1-chloro-3-tri-
fluoromethylbenzene (1.8 g, 10 mmol) affording a colorless
oil; yield: 2.01 g (60%).
1-Bromo-2-iodo-3-trifluoromethoxybenzene: At À758C,
butyllithium (0.10 mol) in hexanes (55 mL) and diisopropyl-
amine (14 mL, 10 g, 0.10 mol) were added successively to
tetrahydrofuran (0.2 L). After 15 min 1-bromo-3-trifluoro-
methoxy-benzene (13 mL, 20 g, 0.10 mmol) was added. The
mixture was kept for 2 h at À758C before a solution of
iodine (25 g, 0.10 mol) in tetrahydrofuran (50 mL) was
added. After addition of a 10% aqueous solution (0.10 L) of
sodium thiosulfate the mixture was extracted with diethyl
ether (3”0.10 L). The combined organic layers were dried
over sodium sulfate before being evaporated to dryness.
Distillation afforded the pure product; yield: 31.92 g (87%).
Trisubstituted Biaryls by Homo-Aryl/Aryl Coupling;
2-Bromo-3’,6-difluoro-2’-iodobiphenyl (9)[29]
At À758C, butyllithium (13 mmol) in hexanes (7.0 mL) was
added to a solution of 1-bromo-3-fluoro-2-iodo-benzene
(7.5 g, 25 mmol) in tetrahydrofuran (50 mL). After 45 min
the mixture was allowed to reach 258C over a two-hour
period. Water (0.10 L) was added to the reaction mixture
followed by extraction with diethyl ether (3”0.10 L). The
combined organic layers were dried over sodium sulfate
before being evaporated to dryness. Upon crystallization
from ethanol, colorless needles were obtained; yield: 3.31 g
(67%).
Disubstituted Biaryls by Homo-Aryl/Aryl Coupling;
2-Bromo-2’-iodobiphenyl (4)[29]
2-Bromo-3’,6-dichloro-2’-iodobiphenyl (10):[29] Prepared
analogously as biphenyl 9 starting from 1-bromo-3-chloro-2-
iodobenzene (16 g, 50 mmol); colorless needles; yield: 8.34 g
(78%).
At À758C, butyllithium (50 mmol) in hexanes (31 mL) was
added to a solution of 1-bromo-2-iodobenzene (13 mL, 28 g,
0.10 mol) in tetrahydrofuran (0.20 L). The mixture was then
warmed to 258C over a two hours period and hydrolyzed
with a 1.0M aqueous hydrochloric acid solution (0.10 L).
After separation of the phases, the aqueous layer was ex-
tracted with diethyl ether (3”0.20 L). The combined organic
layers were dried over sodium sulfate before being evapo-
rated to dryness. Upon crystallization from ethanol, color-
less needles were obtained; yield: 14.54 g (81%).
Trisubstituted Biaryls by Hetero-Aryl/Aryl Coupling;
2,2’-Dibromo-6-fluorobiphenyl (11)[29]
At À758C, butyllithium (50 mmol) in hexanes (24 mL) was
added to a solution of 1-bromo-3-fluoro-2-iodo-benzene
(7.5 g, 25 mmol) in tetrahydrofuran (50 mL). After 45 min
1,2-dibromobenzene (3.0 mL, 5.9 g, 25 mmol) was added to
the mixture. After 2 h at À758C the mixture was allowed to
obtain 258C over a two hours period. Water (0.10 L) was
added to the reaction mixture followed by extraction with
diethyl ether (3”0.10 L). Crystallization from ethanol af-
forded 11 as colorless needles; yield: 6.52 g (79%).
Disubstituted Biaryls by Hetero-Aryl/Aryl Coupling;
2’-Bromo-2-methoxybiphenyl (5)
2-Bromoanisole (4.7 g, 25 mmol) was added to a À758C
cold solution of tert-butyllithium (50 mmol) in pentanes
(30 mL) and tetrahydrofuran (70 mL). After 5 min, the tem-
perature was increased to À258C for 15 min. Then, a solu-
tion of 1,2-dibromobenzene (3.0 mL, 5.9 g, 25 mmol) in tet-
rahydrofuran (10 mL) was added dropwise, over a 10 min
period. The mixture was allowed to reach room temperature
before water (25 mL) was added followed by extraction with
diethyl ether (3”20 mL). The combined organic layers were
dried and evaporated. Column chromatography on silica gel
(20 mL) using cyclohexane as eluent afforded 5. Crystalliza-
tion from ethanol gave colorless needles; yield: 4.41 g
(67%).
2,2’,6-Tribromobiphenyl (12):[29,40,41] Prepared analogously
as biphenyl 11 starting from 1,3-dibromo-2-iodobenzene
(9.0 g, 25 mmol). The residue was purified by flash chroma-
tography which afforded 12 as colorless needles; yield:
4.10 g (42%).
2,2’-Dibromo-6-methoxybiphenyl (13):[40,41] At À1008C,
tert-butyllithium (25 mmol) in pentane (18 mL) was added
to a solution of 3-bromo-2-iodoanisole[45] (3.91 g, 12.5 mmol)
in tetrahydrofuran (50 mL). After 45 min 1,2-dibromoben-
zene (1.5 mL, 3.0 g, 12.5 mmol) was added to the mixture.
After 2 h at À1008C the mixture was allowed to obtain
258C over a twelve-hour period. Water (0.10 L) was added
2’-Bromo-2-trifluoromethoxybiphenyl (6): Trifluorome-
thoxybenzene (4.1 g, 25 mmol) was added to a À758C cold
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to the reaction mixture followed by extraction with diethyl
ether (3”0.10 L). After crystallization from ethanol 2,2’-di-
bromo-6-methoxybiphenyl (13) was obtained as colorless
cubes; yield: 2.05 g (48%).
4,5,2’,6’-tetramethoxybiphenyl (20) as colorless cubes; yield:
1.0 g (55%).
2,6-Difluoro-2’-bromo-3-methoxybiphenyl
(14):
At
Synthesis of Mono- and Diphosphines; 2’,6-
Bis(dicyclohexylphosphino)-2-methoxybiphenyl
(21)[40,41]
À758C, 2,4-difluoroanisole (3.6 g, 25 mmol) was added to a
solution of sec-butyllithium (25 mmol) in cyclohexane
(15 mL) and tetrahydrofuran (35 mL). After 45 min, 1,2-di-
bromobenzene (3.0 mL, 5.9 g, 25 mmol) was added and the
mixture was allowed to reach room temperature in the
course of 12 h. Evaporation of the solvent followed by
column chromatography on silica gel (100 mL) using cyclo-
hexane as the eluent afforded 14 as colorless oil; yield:
6.06 g (81%).
2,6-Difluoro-2’-bromo-4-methoxybiphenyl (15): Prepared
analogously as biphenyl 14 from 3,5-difluoroanisole (3.6 g,
25 mmol) affording colorless needles; yield: 5.83 g (78%).
2,6-Difluoro-3-chloro-2’-bromobiphenyl (16): Prepared
analogously as biphenyl 14 from 1-chloro-2,4-difluoroben-
zene (1.5 g, 10 mmol) affording a colorless oil; yield: 2.06 g
(68%).
2,6-Difluoro-4-chloro-2’-bromobiphenyl (17): Prepared
analogously as biphenyl 14 from 1-chloro-3,5-difluoroben-
zene (1.5 g, 10 mmol) affording a colorless oil; yield: 2.22 g
(73%).
2’-Bromo-3,5,6-trimethoxy-2-methylbiphenyl (18): Pre-
pared analogously as biphenyl 11 starting from 3-bromo-
1,2,5-trimethoxy-4-methylbenzene[46] (2.6 g, 10 mmol). The
pure compound could be obtained by column chromatogra-
phy on silica gel using ethyl acetate/cyclohexane (1:9) as
eluent. Crystallization from ethyl acetate/hexanes (1:5) af-
forded 18 as colorless needles; yield: 1.4 g (42%).
At À758C, butyllithium (0.10 mol) in hexanes (63 mL) was
added to a solution of 13 (17 g, 50 mmol) in tetrahydrofuran
(0.25 L). After 15 min at À758C, the mixture was treated
with
a 2.0M solution of chlorodicyclohexylphosphine
(22 mL, 24 g, 0.10 mol) in toluene (50 mL). The mixture was
allowed to reach 258C and treated with a saturated aqueous
solution of ammonium chloride (0.10 L). The mixture was
extracted with ethyl acetate (3”50 mL), and the combined
organic layers were dried over sodium sulfate. The diphos-
phine 21 was obtained after evaporation of the solvents and
crystallization from methanol (0.10 L) as colorless cubes;
yield: 43 g (74%).
2,6-Difluoro-3-methoxy-2’-dicyclohexylphosphinobiphenyl
(22): Biphenyl 14 (1.5 g, 5.0 mmol) was added to a solution
of tert-butyllithium (10 mmol) in pentanes (6.0 mL) and di-
ethyl ether (15 mL) at À758C. After 15 min at À758C, a so-
lution of chlorodicyclohexylphosphine (1.0 mL, 1.0 g,
5.0 mmol) in tetrahydrofuran (5.0 mL) was added to the re-
action mixture. Evaporation of the solvent followed by
column chromatography on silica gel (100 mL) using cyclo-
hexane as the eluent gave a colorless oil. Crystallization
from methanol afforded colorless needles; yield: 1.83 g
(87%).
2,6-Difluoro-4-methoxy-2’-dicyclohexylphosphino-biphen-
yl (23): As described in the preceding paragraph, starting
from biphenyl 15 (1.5 g, 5.0 mmol) afforded colorless nee-
dles of 23; yield: 1.69 g (81%).
6-Fluoro-2,2’-bis(dicyclohexylphosphino)biphenyl (24):[29]
Biphenyl 11 (1.6 g, 5.0 mmol) was added to a solution of bu-
tyllithium (10 mmol) in hexanes (6.3 mL) and tetrahydrofur-
an (20 mL) at À758C. After 15 min at À758C, a solution of
chlorodicyclohexylphosphine (2.0 mL, 2.0 g, 10 mmol) in tet-
rahydrofuran (10 mL) was added to the reaction mixture.
Evaporation of the solvent followed by column chromatog-
raphy on silica gel (100 mL) using cyclohexane as eluent
gave a colorless oil. Crystallization from ethyl acetate/hex-
anes (1:5) afforded colorless needles; yield: 2.23 g (79%).
Dicyclohexyl-(4,5,2’,6’-tetramethoxybiphenyl-2-yl)phos-
phine (25): At À788C, tert-butyllithium (4.0 mmol) in pen-
tane (2.3 mL) was added dropwise to a solution of 2-bromo-
4,5,2’,6’-tetramethoxybiphenyl (20, 2.0 mmol, 0.7 g) in tetra-
hydrofuran (10 mL). After 1 h, a solution of chlorodicyclo-
hexylphosphine (2.0 mol, 0.5 g, 0.5 mL) in toluene (2.0 mL)
was added dropwise. One hour later, the mixture was al-
lowed to reach 258C and was filtered on silica gel with di-
ethyl ether as eluent. The organic layer was evaporated and
the crude product was purified by chromatography on silica
gel which afforded the monophosphine 25 as a white solid;
yield: 0.07 g (7%).
Tetrasubstituted Biaryls by Homo-Aryl/Aryl
Coupling; 10,10’-Dibromo-[9,9’]biphenanthrenyl
(19)[29]
At À758C, butyllithium (5.0 mmol) in hexanes (3.1 mL) was
added to a solution of 9,10-dibromophenanthrene[47] (3.3 g,
10 mmol) in tetrahydrofuran (20 mL). The mixture was then
warmed to 258C over a two-hour period and hydrolyzed
with a 1.0M aqueous hydrochloric acid solution (0.10 L).
After separation of the phases, the aqueous layer was ex-
tracted with dichloromethane (3”0.20 L). The combined or-
ganic layers were dried over sodium sulfate before being
evaporated to dryness. Upon crystallization from ethanol,
colorless needles were obtained; yield: 1.61 g (63%).
2-Bromo-4,5,2’,6’-tetramethoxybiphenyl (20): At 08C, bu-
tyllithium (5.5 mmol), in hexanes (3.6 mL) was added drop-
wise to a solution of 1,3-dimethoxybenzene (5.5 mmol, 0.8 g,
0.7 mL) in tetrahydrofuran (13 mL). Immediately after com-
plete addition, the solution was allowed to reach 258C.
After 3.5 h, the reaction mixture was cooled to À788C and a
solution of 1,2-dibromo-4,5-dimethoxybenzene[48] (5.0 mmol,
1.5 g) in tetrahydrofuran (2.5 mL) was added dropwise. The
reaction mixture was allowed to reach 258C during a twelve
hours period. Water (10 mL) was added, followed by extrac-
tion with ethyl acetate (4”10 mL). The combined organic
layers were dried over sodium sulfate, filtered and evaporat-
ed. The residue was purified by chromatography on silica
gel and crystallization from methanol affording 2-bromo-
SupportingInformation
For the above procedures with full product characterization,
please refer to the Supporting Information.
2712
asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 2705 – 2713

A Practical Transition Metal-Free Aryl-Aryl Coupling Method
UPDATES
[22] F. R. Leroux, R. Simon, N. Nicod, Lett. Org. Chem.
2006, 3, 948.
Acknowledgements
[23] M. Schlosser, Angew. Chem. Int. Ed. 2005, 44, 376.
[24] F. Leroux, M. Schlosser, E. Zohar, I. Marek, in:
Chemistry of Organolithium Compounds, Vol. 1, (Ed.:
Z. Rappoport), Wiley, Chichester, 2004, p 435.
This work was financially supported by the Schweizerische
Nationalfonds zur Fçrderung der wissenschaftlichen For-
schung, Bern (grant 20–100–332–02), the Bundesamt für Bil-
dung und Wissenschaft, Bern (grant C02.0060 linked to the
COST-D24 project WG0006–02) and the Bundesamt für Ber-
ufsbildung und Technologie, Bern, in the framework of a
KTI project (contract 5474.1 KTS). We are grateful to the
CNRS and Minist›re de la Recherche. F.R.L. is much indebt-
ed to Prof. M. Schlosser, Lausanne, for generous support and
precious advice.
[25] M. Schlosser, in: Organometallics in Synthesis:
A
Manual, (Ed.: M. Schlosser), 2nd edn., Wiley, Chiches-
ter, 2002, pp 1–352.
[26] F. Leroux, N. Nicod, L. Bonnafoux, B. Quissac, F. Colo-
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asc.wiley-vch.de
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