Iron-catalyzed alkylations of aromatic Grignard reagents

Article abstract of DOI:10.1002/anie.200700742

(Chemical Equation Presented) Any old iron: Two efficient iron-catalyzed cross-coupling reactions between aryl Grignard reagents and alkyl bromides were developed that are suitable for large-scale applications. The first procedure uses iron acetylacetonate and involves a cooperative effect between the two ligands N,N,N′,N′-tetramethylethylenediamine (TMEDA) and hexamethylenetetraamine (HMTA), while the second procedure uses [(FeCl ₃)₂(tmeda)₃] as catalyst. 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/anie.200700742

Communications
DOI: 10.1002/anie.200700742
Homogeneous Catalysis
Iron-Catalyzed Alkylations of Aromatic Grignard Reagents**
GØrard Cahiez,* Vanessa Habiak, Christophe Duplais, and Alban Moyeux
Sustainable development now plays an increasingly important
role in the strategy of chemical industries. As a part of this
preoccupation, the search for more economic and more eco-
friendly new efficient synthetic methods is of vital concern.
The development of iron-catalyzed cross-coupling reactions is
one of the current promising fields of research, as these
reactions are very attractive compared to the related palla-
dium- or nickel-catalyzed procedures extensively used until
now. This is well illustrated by the numerous results published
by us[1] and others.[2] Note that for large-scale applications, it is
not enough to use iron salts as catalysts; it is also important to
use cheap ligands in small amounts as well as solvents that are
compatible with industrial processes.
We recently became interested in the iron-catalyzed
alkylation of aromatic Grignard reagents for large-scale
applications. During the course of our studies, some related
reports appeared in the literature. Hayashi and Nagano[3a] and
Bedford et al.[3c,d] reported the cross-coupling reaction
between primary and secondary alkyl bromides and aromatic
Grignard reagents in the presence of catalytic amounts of
FeCl3. The group of Bedford also showed that a [FeCl(salen)]
complex can be used as a catalyst.[3b] However, yields are
generally lower than 80% and the Grignard reagent has to be
used in large excess and added at once. Moreover, the
reactions are performed in diethyl ether under reflux. There-
fore, these methods are not suitable for large-scale applica-
tions.
Two other reports suggested that the coupling could be
carried out in THF. Fürstner[3e] showed that the complex
[Li(tmeda)]2[Fe(C2H4)4] is a very efficient catalyst (TMEDA:
N,N,N’,N’-tetramethylethylenediamine). From a mechanistic
point of view, this elegant example is very interesting as it
demonstrates that a Fe2À species can be used successfully.
However, the use of a sophisticated non-commercial iron
complex is a major drawback for large-scale applications. The
catalytic system used by Nakamura and co-workers[3f] (FeCl3/
TMEDA) seems more attractive. Nevertheless, it is necessary
to use a large quantity of TMEDA (26 equiv relative to
FeCl3). Also, during our investigations we found that the use
of FeCl3 leads to variable yields according to its purity and its
commercial origin (see Supporting Information). Moreover,
this salt is not very easy to handle on a large scale as it is highly
hygroscopic.
Herein, we report our results concerning two new
catalytic systems that can be used on a large scale to perform
this reaction very efficiently.
Nakamura and co-workers reported that the use of
[Fe(acac)3] (acac: acetylacetonate) as a catalyst gave unsat-
isfactory yields of the substitution product.[4] We found this
very surprising because during our investigations the reaction
proceeded very efficiently in the presence of TMEDA and
[Fe(acac)3], whatever the origin of the salt (Scheme 1).
Moreover, these results concord well with our experience in
Scheme 1. Cross-coupling between phenylmagnesium bromide and
cycloheptyl bromide in the presence of [Fe(acac)3].
the field of iron catalysis[1] as the use of [Fe(acac)3] in place of
FeCl3 has always led to more reproducible results and to
similar or better yields. Note that only 10 equivalents of
TMEDA are required when using [Fe(acac)3] as catalyst,
instead of 26 equivalents of TMEDA with FeCl3 (Scheme 2).
Scheme 2. Influence of TMEDA on the iron-catalyzedcross-coupling
reaction between phenylmagnesium bromide and sec-butyl bromide.
[*] Prof. G. Cahiez, V. Habiak, C. Duplais, A. Moyeux
Laboratoire de Synth›se Organique SØlective et de Chimie Orga-
nomØtallique (SOSCO)
We were not satisfied by this result as the amount of
TMEDA was still too high, and so we tested a vast array of
ligands. The most interesting results were obtained with
UMR 8123 CNRS-UCP-ESCOM
5 Mail Gay-Lussac, Neuville s/Oise, 95092 Cergy-Pontoise (France)
Fax: (+33)1-3425-7383
hexamethylenetetraamine (HMTA). Moreover,
a single
E-mail: g.cahiez@escom.fr
equivalent of this ligand suffices to increase the yield up to
80% (Scheme 3). To the best of our knowledge, this is the first
use of HMTA as a ligand in performing a transition-metal-
catalyzed cross-coupling reaction. HMTA is very convenient
for industrial applications as it is a cheap compound that is
easily eliminated then degraded during the treatment of the
effluents.
[**] We thank the CNRS andthe Ecole SupØrieure de Chimie Organique
et MinØrale (ESCOM) for their financial support as well as the
Minist›re de l’Education Nationale et de la Recherche for its
financial support and a grant to A.M. The Fondation de France is
acknowledged for a grant to C.D. and V.H.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
4364
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Angewandte
Chemie
Table 1: Iron-catalyzedcross-coupling between aryl Grignardreagents
and secondary alkyl halides.[a]
Entry
Alkyl halide
Product
Isolated
yield[%]
1
2
3
4
3
4
5
6
91[b]
88[b]
90
Scheme 3. Influence of HMTA or a combination of TMEDA andHMTA
on the iron-catalyzedcross-coupling reaction between phenylmagne-
sium bromide and sec-butyl bromide.
89
5
7
2
83
However, with HMTA it is not possible to obtain the
product in more than 80% yield. Fortunately, we discovered
that by using both one equivalent of HMTA and two
equivalents of TMEDA (Scheme 3) it is possible to obtain a
better yield (92%) than in the presence of only one of these
ligands, whatever their proportion. In fact, this new catalytic
system based on a synergy between two ligands is clearly
more convenient and reliable than the one previously
described by Nakamura and co-workers (FeCl3/TMEDA).[3f]
Recently, in an interesting report, Fu and co-workers[5a]
showed that secondary alkyl halides do not react under
palladium catalysis as the oxidative addition is too slow. They
demonstrated that this lack of reactivity is mainly due to steric
effects. Under iron catalysis, the coupling reaction is clearly
less sensitive to such steric influences as both cyclic and
acyclic secondary alkyl bromides were used successfully
(Table 1). Such a difference could be explained by the
mechanism proposed in Scheme 4. Contrary to Pd0, which
reacts with alkyl halides according to a concerted oxidative
addition mechanism, the iron-catalyzed reaction could
involve a two-step single-electron transfer.
6
7
8
X=I
X=Br
X=Cl
94
93
traces
9
8
9
93
88
10
11
10
67
12
13
11
12
88
71
14
15
13
14
85
74
Secondary alkyl bromides or iodides gave rise to similar
yields (Table 1, entries 6 and 7). However, no reaction
occurred with the corresponding chlorides (Table 1, entry 8).
Our cross-coupling conditions were also successfully applied
to primary alkyl halides (Table 2). Generally, the yields were
lower than those obtained from secondary alkyl bromides,
[a] The aryl Grignard reagent (13 mmol) was added dropwise over
45 min to a solution of alkyl bromide (10 mmol), [Fe(acac)3] (0.5 mmol),
TMEDA (1.0 mmol), andHMTA (0.5 mmol) in THFat 0 8C under stirring.
[b] The reaction was performedon a 50 mmol scale.
especially with long-chain alkyl bromides such as dodecyl
bromide (Table 2, entries 5 and 6).
During our investigations, we also tried to eliminate the
drawbacks previously mentioned with FeCl3. Indeed, this salt
is interesting as it is a very cheap material. After several
attempts, we finally discovered that it is very easy to obtain a
complex [(FeCl3)2(tmeda)3] by adding 1.5 equivalents of
TMEDA to a solution of FeCl3 in THF at room temperature.
The complex precipitates and can be isolated quantitatively
by filtration. To our delight, only 1.5 mol% [(FeCl3)2-
(tmeda)3] was needed to perform the coupling between an
aromatic Grignard reagent and a secondary alkyl halide very
efficiently (Table 3, entries 1–4). The reaction can be
extended to primary alkyl halides, but the yields are generally
slightly lower (Table 3, entry 5).
This procedure compares very advantageously to the one
Scheme 4. Tentative mechanism for the iron-catalyzedcoupling reac-
tion.[6]
previously described by Nakamura and co-workers.[3f] The
Angew. Chem. Int. Ed. 2007, 46, 4364 –4366
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www.angewandte.org
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Communications
Table 2: Iron-catalyzedcross-coupling between primary alkyl bromides
[a]
andaromatic Grignardreagents.
Entry
Alkyl halide
Product
Yield
[%]
1
2
3
15
16
17
75[b]
70[b]
76
4
5
6
18
19
20
72
50
39
Scheme 5. Large-scale preparation of sec-butylbenzene.
non-hygroscopic and cheap complex that is very easy to
prepare.
[a] The aryl Grignard reagent (13 mmol) was added dropwise over
45 min to a solution of alkyl bromide (10 mmol), [Fe(acac)3] (0.5 mmol),
TMEDA (1.0 mmol), andHMTA (0.5 mmol) in THFat 0 8C under stirring.
[b] The reaction was performedon a 50 mmol scale.
Received: February 18, 2007
Published online: April 30, 2007
Keywords: cross-coupling · Grignardreagents ·
.
homogeneous catalysis · iron · sustainable chemistry
Table 3: Cross-coupling between aryl Grignardreagents andsecondary
alkyl halides[a] in the presence of [(FeCl3)2(tmeda)3].
Entry
Alkyl halide
Product
Yield
[%]
[1] a) G. Cahiez, P. Y. Chavant, E. Metais, Tetrahedron Lett. 1992, 33,
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1
2
2
9
81
92
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[2] For exhaustive reviews on iron-mediated coupling reactions, see:
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5
5
91
75
15
[a] The aryl Grignard reagent (13 mmol) was added dropwise over
45 min to a solution of alkyl bromide (10 mmol) and [(FeCl3)2(tmeda)3]
(0.15 mmol) in THF at room temperature under stirring.
2004, 116, 4045; Angew.Chem.Int.Ed.
2004, 43, 3955; f) M.
Nakamura, K. Matsuo, S. Ito, E. Nakamura, J.Am.Chem.Soc.
2004, 126, 3686.
[4] See reference [3f] and Table S2 in the Supporting Information.
[5] a) I. D. Hills, M. R. Netherton, G. C. Fu, Angew.Chem. 2003, 115,
5927; Angew.Chem.Int.Ed. 2003, 42, 5749. For general reviews
on the use of alkyl halides to perform cross-coupling reactions,
see: b) A. C. Frisch, M. Beller, Angew.Chem. 2005, 117, 680;
Angew.Chem.Int.Ed. 2005, 44, 674; c) M. R. Netherton, G. C.
Fu, Adv.Synth.Catal. 2004, 346, 1525; d) D. J. Cꢀrdenas, Angew.
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references therein.
amount of TMEDA required is dramatically lowered (from
120% to 5%) and 3% FeCl3 is used instead of 5%. In
addition, the yields are slightly better (5–10% higher) and the
coupling is performed at room temperature instead of 08C.
Finally, note that contrary to FeCl3, the complex [(FeCl3)2-
(tmeda)3] is not hygroscopic and can be stored at room
temperature without any special precautions.
Finally, we applied our cross-coupling procedures on a
large scale. The results (unoptimized yields) are described in
Scheme 5.
In summary, we have disclosed herein two efficient eco-
friendly iron-catalyzed procedures to couple secondary and
primary alkyl halides with aromatic Grignard reagents, using
two new catalytic systems, [Fe(acac)3]/HMTA/TMEDA
(1:1:2) and the complex [(FeCl3)2(tmeda)3]. To the best of
our knowledge, HMTA has never been employed as a ligand
for cross-coupling reactions until now, while the second
catalyst [(FeCl3)2(tmeda)3] has not been described and is a
[6] The mechanism is based on the Fe0/FeII couple. A similar catalytic
cycle can also be written by using a FeI/FeIII couple (see S. M.
Neumann, J. K. Kochi, J.Org.Chem. 1975, 40, 599 and R. S.
Smith, J. K. Kochi, J.Org.Chem. 1976, 41, 502) or a FeÀII/Fe0
couple as recently proposed (A. Fürstner, A. Leitner, M. Mꢁndez,
H. Krause, J.Am.Chem.Soc. 2002, 124, 13856; A. Fürstner, A.
Leitner, Angew.Chem. 2002, 114, 632; Angew.Chem.Int.Ed.
2002, 41, 609). Iron ate complexes have been isolated recently:
a) A. Fürstner, H. Krause, C. W. Lehman, Angew.Chem. 2006,
118, 454; Angew.Chem.Int.Ed.
2006, 45, 440; b) P. J. Alonso,
A. B. Arauzo, J. Forniꢁs, M. A. Garcꢂa-Montforte, A. Martꢂn, J. I.
Martꢂnez, B. Menjꢃn, C. Rillo, J. J. Sꢀiz-Garitaonandia, Angew.
Chem. 2006, 118, 6859; Angew.Chem.Int.Ed.
2006, 45, 6707.
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