Iron-catalyzed homocoupling of aryl halides and derivatives in the presence of alkyllithiums

Article abstract of DOI:10.1021/ol401987s

Direct synthesis of biaryl derivatives from aryl halides takes place under very mild temperature conditions by using a ligand-free iron catalytic system. The procedure, which proceeds via an in situ quantitative aryl halide exchange with alkyllithiums, allows for excellent control of the reactivity and is in line with the sustainable development. The method is also applicable to styryl and benzyl halides and to phenylacetylene.

Full text of DOI:10.1021/ol401987s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Iron-Catalyzed Homocoupling of Aryl
Halides and Derivatives in the Presence
of Alkyllithiums
Dounia Toummini,† Fouad Ouazzani,‡ and Marc Taillefer*,†
Institut Charles Gerhardt Montpellier, ENSCM, 8 rue de l’Ecole Normale,
34296 Montpellier Cedex 5, France, and Laboratoire de Chimie Organique Appliquee,
ꢀ
ꢁ
FST Fes BP 2202, 30.000 Fes, Maroc
ꢁ
marc.taillefer@enscm.fr
Received July 17, 2013
ABSTRACT
Direct synthesis of biaryl derivatives from aryl halides takes place under very mild temperature conditions by using a ligand-free iron catalytic
system. The procedure, which proceeds via an in situ quantitative aryl halide exchange with alkyllithiums, allows for excellent control of the
reactivity and is in line with the sustainable development. The method is also applicable to styryl and benzyl halides and to phenylacetylene.
In the last decades, symmetrical and unsymmetrical
biaryls have received increased attention as privileged
structures for the agrochemical and pharmaceutical
industries.1 Many classes of natural products2 and optical
materials and organic conductors3 involve the biaryl unit.
Ullmann first reported in 1901 the synthesis of biaryl units
from the copper-mediated coupling of aryl halides per-
formed under harsh reaction conditions.4,5 The first evolu-
tion in this field occurred 70 years later and consisted of the
use of stoichiometric amounts of nickel instead of copper
in a traditional Ullmann-like procedure. Then systems
based on nickel catalysts appeared, with the works of
Kumada6 and Corriu7 involving the coupling of aryl
halides and aromatic Grignards. The latter were next used
with palladium, and the procedure was also extended to
zinc, tin, and boron derivatives in the Negishi, Stille, and
Suzuki reactions. As far as the synthesis of symmetrical
biaryls is concerned, studies recently have been reported.
The homocoupling of Grignard reagents has, for example,
been described by Hayashi and Cahiez for the preparation
of biaryl units. These authors used iron salts (FeCl3) as
catalysts and dihalogenoethane8,9 or dry air10 as the oxi-
dant. Xu also developed a Fe(acac)3-catalyzed procedure
from arylmagnesiums under oxidant-free conditions.11
The homocoupling of aryllithium derivatives also permits
to obtain symmetrical biaryls. While studying the NiBr2-
(bpy)2 catalyzed cross-coupling of phenyllithium with aryl
chlorides, we observed the formation of biphenyl 1 result-
ing from the nickel-catalyzed homocoupling of PhLi.12
† Institut Charles Gerhardt Montpellier.
‡
ꢀ
Laboratoire de Chimie Organique Appliquee.
(8) Nagano, T.; Hayashi, T. Org. Lett. 2005, 7, 491.
(9) Cahiez, G.; Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M. Org.
Lett. 2005, 7, 1943.
(1) Horton, D. A.; Bourne, G. T.; Smythe, L. M. Chem. Rev. 2003,
103, 893.
(2) Baudoin, O.; Gueritte, F. Stud. Nat. Prod. Chem 2003, 29, 355.
(3) Nielsen, M. B.; Diederich, F. Chem. Rev. 2005, 105, 1837.
(4) Ullmann, F.; Bielecki, J. Chem. Ber 1901, 34, 2174.
(10) Cahiez, G.; Moyeux, A.; Buendia, J.; Duplais, C. J. Am. Chem.
Soc. 2007, 129, 13788.
(11) Xu, X.; Cheng, D.; Pei, W. J. Org. Chem. 2006, 71, 6637.
(12) Confirmed in the blank experiments performed without aryl
ꢀ
(5) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359.
ꢀ
halides (a) Taillefer, M.; Bouchitte, C.; Cristau, H. J.; Schlama, T.;
Spindler, J. F. (Rhodia) Fr 2000 01787 (WO 01/58834). (b) Bouchitte,
C.; Cristau, H. J.; Spindler, J. F.; Taillefer, M. Thesis, Nickel catalyzed
ꢀ
biaryl synthesis from aryl halides and aryllithium derivatives, Universite
de Montpellier II, 2000.
(6) (a) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc.
1972, 94, 4374. (b) Kumada, M. Pure. Appl. Chem. 1980, 52, 669.
(7) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem. Commun. 1972,
144.
ꢀ
r
10.1021/ol401987s
XXXX American Chemical Society

Later, the same NiCl2(bpy)2 precatalyst and strategy
were reported13 for the synthesis of symmetrical biaryl
units, and more recently, a similar route was applied from
vanadium catalysts.14 A procedure for homocoupling from
aryllithium reagents was also described by Iyoda using
stoichiometric amounts of the Lipshutz cuprate15 in combi-
nation with 1,4-benzoquinone as the electron acceptor.16
Stoichiometric amounts of copper17 or palladium18 catalysts
were also employed for the synthesis of symmetrical biaryls
from arylboronic acids. In addition, during the redaction of
this paper, Severin et al. presented an original development
of the magnesium route by using nitrous oxide as oxidant in
the iron catalyzed homocoupling of Grignard reagents.19
Here, we report a new method allowing for the synthesis
ofvarioussymmetrical biarylunits via anhomocouplingof
aryl lithium derivatives, in situ generated from aryl halides.
We used a very simple iron-based catalytic system (FeCl2),
inwhich thislesstoxic and inexpensivemetal isusedin mild
temperature (25 °C) and under ligand-free conditions, in
the absence of any additional oxidant.
Transposing these conditions in the more environmen-
tally friendly THF also exclusively afforded biphenyl
while using a smaller amount of Et3N (0.5 equiv)
lowered the yield (Table 1, entries 12 and 13). Note
that excellent and good yields in 1 were obtained with
commercial solutions of linear s-BuLi (2-Li-butane) or
n-BuLi at lower concentrations (1.6 equiv; entries 14
and 15). Finally, quantitative and fair yields in biphenyl
1 were obtained from iodobenzene and challenging
chlorobenzene respectively (entries 19 and 20).
Table 1. Fe-Catalyzed Synthesis of Biphenyl 1 from
Bromo-, Iodo-, or Chlorobenzene in the Presence of
t-BuLi or of Linear n- or s-BuLia
We first tried to perform iron-catalyzed homocoupling
of phenyllithium itself. We observed that a simple salt such
as FeCl2 was able to afford the corresponding biphenyl 1
under mild and ligand-free conditions in an interesting
although fair yield (50%).
entry
X
[Fe]
additive
solvent
yieldb (%)
1
Br
I
FeCl2
FeCl2
FeCl2
Fe
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
THF
32
2
45
3
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
22
4
31
5
FeCl3
Fe(acac)3
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
50
6
46
7
1,10-phen
DABCO
Bu3N
8
We then tested the possibility of applying this reaction
starting directly from phenyl halides via an in situ generation
of phenyllithium (Table 1). The preliminary survey, carried
out with various solvents and iron sources, allowed us
to identify an efficient catalytic system for the synthesis of
biphenyl 1. The first reaction was performed with bromo-
benzene (1 equiv), t-BuLi (2 equiv added at ꢀ78 °C), and
FeCl2 (10 mol %) in benzene at 25 °C for 4 h. A low yield
was obtained, as it was also the case starting from iodo- or
chlorobenzene (Table 1, entries 1ꢀ3). The other iron
sources tested (Fe, FeCl3 or Fe(acac)3) only permitted to
slightly improve the system with a maximum of 50% yield in
biphenyl 1 (Table 1, entries 4ꢀ6). The presence of addi-
tive (1 equiv) such as phenanthroline, 1,4-diazabicyclo-
[2.2.2]octane (DABCO), or tributylamine (Bu3N) was un-
successful at enhancing the yield. The first significant
improvement was observed when tetramethylethylenedia-
mine (TMEDA) was added in the medium, thus affording
70% of biphenyl (Table 1, entries 7ꢀ10). Eventually, we
were pleased to find that the use of the simple triethylamine
(Et3N) as additive led quantitatively to 1 (Table 1, entry 11).
8
13
9
54
10
11
12
13
14
15
16
17
18
19
20
TMEDA
Et3N
70
96
Et3N
100, 100c
58d
96
Et3N
THF
Et3N
THF
Et3N
THF
68
THF
37
Et3N
Et3N
Et3N
Et3N
THF
0
FeCl3
FeCl2
FeCl2
THF
67
THF
100
55
Cl
THF
a Reaction performed with 1 mmol of PhX, 2 equiv of t-BuLi (general
case), or 1.6 equiv of s-BuLi or n-BuLi (entries 14 and 15). b GCMS yield
calculated with undecane as standard. c PhBr was added 1 h after t-BuLi.
d Reaction with 0.5 mmol of Et3N.
An important feature of organolithium derivatives is
the strong relationship between their degree of aggregation
and their reactivity.20 The latter, which evolves in the same
manner as their solubility, can be increased by deaggregation
in donor solvents (Et2O, THF) in the presence of Lewis bases,
particularly of the nitrogen type. This general feature seems to
be supported by the spectacular influence of the NEt3 additive
in THF (Table 1), which could favor the aryl halide exchange
or the further reactivity of an in situ formed phenyllithium.
Next, we explored the breadth of application of this
method by using the conditions optimized in the model
(13) Jhaveri, S. B.; Carter, K. R. Chem.;Eur. J. 2008, 14, 6845.
(14) Lu, F. Tetrahedron. Lett. 2012, 53, 2444.
(15) Lipshutz, B. H.; Wilhelm, R. S.; Floyd, D. M. J. Am. Chem. Soc.
1981, 103, 7672.
(16) Miyake, Y.; Wu, M.; Rahman, M. J.; Iyoda, M. Chem. Commun.
2004, 62, 411.
(17) Demir, A. S.; Reis, O.; Emrullahoglo, M. J. Org. Chem. 2003, 68,
10130.
(18) Nising, C. F.; Schmid, U. K.; Nieger, M.; Brase, S. J. Org. Chem.
2004, 69, 6830.
(19) Kiefer, G.; Jeanbourquin, L.; Severin, K. Angew. Chem., Int. Ed.
€
(20) Gessner, V. H.; Daschlein, C.; Strohmann, C. Chem.;Eur. J.
2013, 52, 6302.
2009, 15, 3320.
B
Org. Lett., Vol. XX, No. XX, XXXX

reaction (Table 1, entries 12 and 14). The system FeCl2/
Et3N in the presence of t-BuLi (2 equiv) or of the more
convenient linear s-BuLi (1.4ꢀ1.6 equiv), efficiently pro-
moted the homocoupling of aryl bromides with electron-
donating (EDG) groups, to afford the corresponding
biaryls in excellent yields. With bromotolyl derivatives,
the reaction was successfully performed whatever the
position of the methyl substituent either ortho, meta or
para (Table 2, entries 2ꢀ4). Similarly, the three possible
bromoanisyl regioisomers also led to the corresponding
biaryls with very good yields (Table 2, entries 5ꢀ7). The
dimethylamino substituent (para) was also an excellent
candidate for the synthesis of the corresponding homo-
coupling product 8 (Table 2, entry 8). Subsequently, we
performed the coupling with aryl bromides bearing electron-
withdrawing groups (EWD) and started with the
p-bromotrifluoromethylbenzene. We obtained the homo-
coupling product but the NMR spectra showed the pre-
sence of a mixture of the para and meta isomers 9/10 (ratio
4/1) (Table 2, entry 9). Interestingly, the synthesis of biaryl
ether 9 could be selectively achieved using p-iodotrifluoro-
methylbenzene as the starting halide (entry 10). This
result might be related to the lithium-halide interchange
rate, known to decrease following the order I > Br > Cl.21
The meta and the sterically demanding o-iodotrifluoro-
methylbenzenes also allowed for the synthesis of the
corresponding m-biaryl 10 and of the challenging o-biaryl
11 (entries 11 and 12).
Table 2. Fe-Catalyzed Synthesis of Biaryls from Aryllithiums,
Generated in Situ from Aryl Halides and s-BuLi or t-BuLia
Two other o-biaryls, o,o0-dicyanobiphenyl 12 and
o,o0-quaterphenyl 13, were obtained in good to excellent
isolated yields (entries 13 and 14), from o-cyanobromo-
benzene and o-bromobiphenyl, respectively. Finally, bi-
naphthyl 14 was obtained from o-bromonaphthalene
(entry 15), and an interesting regioselectivity was observed
with 1-iodo-4-fluorobenzene as the starting substrate.
Indeed, the reaction led to the exclusive formation of
p,p0-difluorobiphenyl 15 (entry 16), thus allowing further
functionalization of aromatic cycles.
The method (with s-BuLi or t-BuLi) was then success-
fully applied to the synthesis of heteroaromatic molecules
suchasbipyridine 16(table 3, entry 1). The same procedure
also allowed the coupling of alkenes and alkynes. There-
fore, the reaction performed from the β-bromostyrene
(commercial mixture of E/Z = 50/50) selectively led to
the E,E-1,4-diphenylbutadiene 17 (Table 3, entry 2). Re-
markably, none of the other possible isomers were ob-
served in the course of the reaction likely attesting to Fe-
catalyzed isomerization steps. In this case, the sole bypro-
duct observed was 1,4-diphenylbut-2-ene (4 mol %). From
phenylacetylene, the resulting homocoupling product 18
(1,4-diphenylbutadiyne) was also obtained in good yield
(Table 3, entry 3); the lithiation was directly performed
without requiring the presence of a halide derivative
as starting partner.22 By this method, we could also
readily obtain 9,10-dihydrophenanthrene 20, from which
a Reaction performed on 1 mmol scale: FeCl2 99.998% (Aldrich) and
FeCl2 99.5% (Alfa Aesar). b Isolated yields. c The para/meta isomers
9/10 are obtained in a 4/1 ratio.
phenanthrene is obtained by a well-described oxidative
dehydrogenation.23 The molecule results from the double
intramolecular and concomitant homocoupling of the com-
mercial 2-bromobenzylbromide, performed in only one step
(23) (a) Zhang, W.; Ma, H.; Zhou, L.; Sun, Z.; Du, Z.; Miao, H.; Xu
J. Molecules 2008, 13, 3236. (b) Kamata, K.; Kasai, J.; Yamaguchi, K.;
Mizuno, N. Org. Lett. 2004, 6, 3577. (c) Tanaka, H.; Ilkeno, T.; Yamada,
T. Synlett 2003, 576.
(21) Gilman, H.; Langham, W.; Moore, F. W. J. Am. Chem. Soc.
1939, 61, 106.
(22) Engman, L.; Stern, D. Organometallics 1993, 12, 1445.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Fe-Catalyzed Coupling of Heteroaryl Halides,
Styryl Halides, Alkynes, Benzyl Bromide, or
2-Bromomethylbromobenzenea
Scheme 1. Fe-Catalyzed Synthesis of the Biaryls from
Aryllithium Derivatives via o-Metalation
functional groups sensitive to harsher conditions.26 Addi-
tionally, the use of alkyllithiums (commercially available
solution) for the synthesis of aryllithiums limits the risks at
the industrial level, compared with for example the corre-
sponding preparation of arylmagnesium derivatives. The
latter can indeed be prevented by traces of water or solvent
(alcohol or ketone) present in multistep syntheses. This
generates a risk for the process, as magnesium may accumu-
late in the reactor and the reaction thereafter may run out
of control, if it finally starts. With the use of alkyllithiums,
the first liters added in the reactor vessel neutralize these
potentially interfering products and the aryllithium expected
is then immediately formed in mild conditions.26 At the
laboratory scale we used t-BuLi or the linear s-BuLi. For
industrial applications, it is clear that the latter or n-BuLi
would be chosen for pilot plant implementation.
In conclusion, we have discovered an efficient method in
which the direct synthesis of symmetrical biaryl derivatives
from aryl halides is possible in very mild temperature
conditions by using a ligand-free iron catalytic system. The
procedure, which proceeds via an in situ quantitative aryl
halide exchange with alkyllithiums, allows for an excellent
control of the reactivity for the further synthesis of the
products. The method is also applicable to styryl and benzyl
halides and to phenylacetylene. Iron is one of the most
abundant metals on earth and one of the most inexpensive
and environmentally friendly ones. For all these reasons this
procedure is in line with sustainable development. Work is in
progress to generalize its application field to dissymmetric
biaryls12,27 and to understand the mechanism.28
a Reaction performed on 1 mmol scale: FeCl2 99.998% (Aldrich) and
FeCl2 99.5% (Alfa Aesar). b Isolated yields. c 4 mol % of 1,4-diphenyl-
but-2-ene was also obtained. d Yield in the absence of iron salt.
via an in situ lithiation of the benzylic and the phenyl posi-
tions (global yield: 76%, entry 5). Note that with the
magnesium route, three successive steps are required for
the same transformation.24 The related benzylbromide itself
led in our conditions to the corresponding homocoupling
molecule 19 with an excellent yield (Table 3, entry 4). Sur-
prisingly,25 this reaction performed without iron also afforded
the product, although in lower yield (Table 3, entry 4).
For the synthesis of o,o0-biaryls, we also developed a
complementary strategy. In a one-pot procedure, both the
ortho lithiation of aromatic compounds (with s-BuLi or
t-BuLi) and their iron-catalyzed homocoupling were ob-
tained (Scheme 1). The method was successfully applied in
preliminary tests to anisole and trifluoromethylbenzene
but failed with benzonitrile for which the homocoupling
from the o-cyanobromobenzene is possible by the former
method (see Table 2, entry 13).
Acknowledgment. We thank the CNRST and the ANR
for a Ph.D. grant for D.T.
The in situ aryl halide exchange with alkyllithiums, the
starting point of our method, displays interesting features
compared to the classical insertion reaction with Li or Mg
metals. It is characterized by mild reaction conditions and
few byproducts especially in the case of substrates involving
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(24) From the same starting 2-bomobenzyl bromide, 20 was also
obtained by the magnesium way in three steps via the following: (i)
homocoupling of an in situ formed benzyl Grignard; (ii) iodination of
two aromatic bromide positions and iron catalyzed homocoupling of an
in situ formed aryl magnesium(global yield: 19%): Cahiez, G.; Chaboche,
C.; Mahuteau-Betzer, F.; Ahr, M. Org. Lett. 2005, 7, 1943.
(25) In the recent literature, homocoupling of the benzyl bromide
takes place via an in situ formation of the benzyl Grignard and the
intervention of manganese and iron catalysts: (a) Xu, X.; Cheng, D.; Pei,
W. J. Org. Chem. 2006, 71, 6637. (b) Cahiez, G.; Moyeux, A.; Buendia,
J.; Duplais, C. J. Am. Chem. Soc. 2007, 129, 13788. (c) Yuan, Y.; Bian, Y.
Appl. Organometal. Chem. 2008, 22, 15.
(27) During the preparation of this manuscript the Pd-catalyzed
cross-coupling of aryl halides with organolithium derivatives was pub-
lished. This Palladium variant of the nickel system we described in ref 12
involves a strategy based on preformed aryllithiums, on halogenꢀ
lithium exchanges, and on direct metalations (as in the Fe-catalytic
system descibed in this paper for the homocoupling): Giannerini, M.;
Fananas-Mastal, M.; Feringa Ben, L. Nat. Chem. 2013, 5, 667.
(28) We identified two possible catalytic cycles including Fe(0)- and
Fe(II)-catalytic species for this reaction. They are presented together
with some mechanistic tests and the corresponding discussion in the-
Supporting Information.
(26) Wakefield, B. J. Organolithium Methods; Academic Press: New
York, 1990.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX