Iron-catalyzed oxidative heterocoupling between aliphatic and aromatic organozinc reagents: A novel pathway for functionalized aryl-alkyl cross-coupling reactions

Full text of DOI:10.1002/anie.200900175

Angewandte
Chemie
DOI: 10.1002/anie.200900175
Synthetic Methods
Iron-Catalyzed Oxidative Heterocoupling Between Aliphatic and
Aromatic Organozinc Reagents: A Novel Pathway for Functionalized
Aryl–Alkyl Cross-Coupling Reactions**
Gꢀrard Cahiez,* Laura Foulgoc, and Alban Moyeux
Iron-catalyzed aryl–alkyl coupling reactions have been exten-
sively studied throughout the past ten years.[1–4] These
reactions can be performed by coupling aryl Grignard
reagents with alkyl halides[2] or alkyl Grignard reagents with
aryl halides.[3] Aryl zinc compounds have also been used.[4] We
report herein a new type of aryl–alkyl coupling; the iron-
catalyzed oxidative heterocoupling between aliphatic and
aromatic diorganozinc reagents.
We believed that this unexpected byproduct resulted from
an oxidative heterocoupling reaction between an arylzinc and
an isopropylzinc species. We confirmed this hypothesis by
treating phenylisopropylzinc with 1,2-dibromoethane as an
oxidant, in the presence of iron(III) acetylacetonate, which
gave isopropylbenzene in 58% yield (Scheme 2). The pres-
Examples of metal-mediated oxidative heterocoupling
reactions have, to date, been rare. Lipshutz and co-workers[5]
À
showed that unsymmetrical biaryls, Ar Ar’, can be obtained
in good yields by oxidation, at low temperature, of a kinetic
high-order cyanocuprate ArAr’Cu(CN)Li2 with oxygen.
More recently, Knochel and co-workers[6] prepared various
phenylacetylene derivatives by oxidation of lithium aryl-
(alkynyl) cuprates with chloranil. In fact, the palladium-
catalyzed oxidative heterocoupling of alkyl zinc halides with
alkynylstannanes, using desyl chloride as an oxidant, is the
only catalytic procedure of this type reported to date.[7] No
examples of aryl–alkyl oxidative coupling reactions have been
reported. Moreover, no examples of oxidative heterocoupling
reaction under iron-catalysis are known.
Scheme 2. Iron-catalyzed oxidative heterocoupling of iPrZnPh.
ence of N,N,N’,N’-tetramethylethylenediamine (TMEDA) in
the reaction was not necessary.
Encouraged by this result, we attempted to couple
diphenylzinc with diisopropylzinc under the same condi-
tions.[9] In spite of our efforts, only one phenyl group and one
isopropyl group were transferred (Scheme 3). This result was
In the course of our investigations on iron-catalyzed cross-
coupling reactions,[8] we obtained an intriguing result. Phenyl-
isopropylzinc reacted with 2-bromooctane in the presence of
[Fe(acac)3] to selectively form 2-phenyloctane in 81% yield.
However, isopropylbenzene was also produced in 11% yield
(Scheme 1).
Scheme 3. Iron-catalyzed oxidative heterocoupling of Ph2Zn with
iPr2Zn.
not surprising, since only 9% of
isopropylbenzene was obtained
by coupling phenyl- and isopro-
pylzinc chlorides under the same
conditions.
The loss of half of the starting
diorganozinc compounds is
clearly a drawback, especially
Scheme 1. Iron-catalyzed cross-coupling reaction between PhZnMe and 2-bromooctane.
when valuable organic groups are used. Therefore, we
turned our attention to mixed diorganozinc compounds
bearing an inexpensive nontransferable group.[10] In theory,
these compounds can be obtained by performing two
successive transmetalations with two different Grignard
reagents.[11]
Initially, we used Me3SiCH2 as the nontransferable group,
as proposed by Nakamura and co-workers.[4] The phenyl and
the isopropyl groups were selectively transferred from
PhZnCH2SiMe3 and iPrZnCH2SiMe3 but isopropylbenzene
[*] Dr. G. Cahiez, L. Foulgoc, A. Moyeux
Department of Chemistry (FRE 3043), CNRS–Universitꢀ de Paris 13
74 Rue Marcel Cachin, 93017 Bobigny (France)
E-mail: gerard.cahiez@univ-paris13.fr
[**] We thank the CNRS for a financial support as well as the Ministꢁre
de l’Education Nationale et de la Recherche for financial support
and a grant to A. Moyeux.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900175.
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Table 1: Oxidative heterocoupling between aromatic and aliphatic
diorganozinc reagents.
was obtained in only 54% yield. Various other groups
(PhCOO, Et2N, tBu) were tested as nontransferable groups
without success.[10] The reaction generally led to low yields
and no selectivity. However, a very interesting result was
obtained by using a simple methyl group, which was as
efficient as Me3SiCH2 but cheaper.[10] As a rule, mixed
organozinc reagents, such as RZnCH2SiMe3 or RZnMe
(R = Ph, iPr), are less reactive than the corresponding
diorganozinc reagents. Thus, the reaction times are five to
ten times longer and the yields of coupling products are lower.
We tried to improve the yields by using an unsymmetrical
diorganozinc species bearing a nontransferable methyl group
and a more reactive symmetrical diorganozinc species
(Scheme 4). This attempt afforded isopropylbenzene in a
À
Entry
1
Ar ZnMe 1
R2Zn 2[a]
Yield [%][b]
79[c]
2
2a
67
3
4
1a
1b
76[c]
68
2b
2b
5
22[c]
Scheme 4. Iron-catalyzed oxidative heterocoupling of PhZnMe with
iPr2Zn.
6
7
8
1b
1b
1b
34
68
71
satisfactory yield of 79%. Moreover, similar results were
obtained by using 10 mol% of catalyst instead of 15 mol%.
These promising preliminary results prompted us to explore
the scope of this reaction (Table 1). The oxidative hetero-
coupling reaction between arylmethylzinc reagents 1 and
secondary dialkylzinc (R2Zn) reagents 2 generally led to
satisfactory yields (Table 1, entries 1–4, 7, and 8). Interest-
ingly, primary dialkylzinc reagents were also used successfully
(Table 1, entries 9 and 10). The reaction seemed rather
sensitive to steric hindrance, as illustrated by the low yield
obtained from the coupling of o-anisylmethylzinc 1c (Table 1,
entry 5). Finally, the reaction could not be extended to
symmetrical benzyl-, allyl-, or tertiary alkylzinc coupling
partners (Table 1, entries 12–14).
9
1b
1a
69
72
10
11
2g
31
12
13
14
1b
1b
1a
6[b]
8[c]
5[b]
Organozinc compounds are known to be very chemo-
selective. Nakamura and co-workers recently reported that
functionalized arylzinc reagents, ArFGZnCH2SiMe3 (ArFG
=
functionalized aryl group), prepared from the Grignard
reagents ArFGMgCl, could be coupled with secondary alkyl
halides under iron catalysis in good yields.[4] However, this
reaction requires two equivalents of the valuable starting
Grignard reagent prepared by halogen/magnesium
exchange[12] with iPrMgCl. We decided to develop a more
economical procedure by using the oxidative heterocoupling
method previously disclosed.
[a] One equivalent of R2Zn was used. R=alkyl; [b] yield of isolated
product; [c] yield determined by GC using decane as an internal
standard.
Phenylmagnesium chloride was prepared by iodine/mag-
nesium exchange from iodobenzene and isopropylmagnesium
chloride, for use in a preliminary experiment.[11] It was then
transmetalated with methylzinc chloride, prepared from
MeMgCl and ZnCl2, to give phenylmethylzinc, which was
then coupled with symmetrical sec-butylzinc (under the
conditions described above) in an oxidative heterocoupling
procedure (Scheme 5). Unfortunately, the reaction led to the
expected sec-butylbenzene in only 51% yield (instead of 76%
in the absence of iPrI). Moreover, the cross-coupling reaction
between phenylmethylzinc and isopropyl iodide, which
formed during the preparation of the starting Grignard
Scheme 5. Use of PhMgCl prepared by I/Mg exchange with iPrMgCl.
reagent, took place competitively, forming isopropylbenzene
in 33% yield.
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Owing to our experience in the field of iron-catalyzed
coupling reactions involving secondary alkyl halides, we knew
the reactivity of these species to be very sensitive to steric
factors.[13] Thus, we performed the iodine/magnesium
exchange by using 3-pentylmagnesium chloride, instead of
isopropylmagnesium chloride. This attempt was successful
since the oxidative heterocoupling reaction was not perturbed
by the presence of 3-iodopentane (Scheme 6). To our knowl-
The preparation of the functionalized alkylmethylzinc 3
(Scheme 8) was not obvious and requires some clarification.
Indeed, the reaction of the alkylzinc iodide IZn-
(CH2)3COOEt with methylmagnesium halide or methyl-
lithium was not chemoselective and afforded poor yields of
3. Interestingly, we discovered that the addition of trimethyl-
manganate Me3MnMgCl (0.33 equivalents) led to quantita-
tive yields of 3.[16]
In summary, we have disclosed herein the first iron-
catalyzed oxidative cross-coupling reaction. The coupling
product was obtained by treating a mixture of aryl- and
alkylzinc reagents with 1,2-dibromoethane in the presence of
[Fe(acac)3]. Primary or secondary aliphatic diorganozinc
reagents were both applicable to this reaction. Good yields
were obtained under mild conditions (no ligand, room
temperature, 3–6 h). Notably, functionalized aryl- or alkylzinc
reagents were both used successfully. Such a reaction paves
the way to a new class of coupling reactions, complementary
to the classical cross-coupling procedures between an organ-
ometallic reagent and an organic halide.
Scheme 6. Use of PhMgCl prepared by I/Mg exchange with
Et2CHMgCl.
Received: January 11, 2009
Published online: March 13, 2009
edge, it is the first use of this Grignard reagent to achieve an
iodine/magnesium exchange.
This procedure was also applied to the coupling of
functionalized arylzinc compounds (Scheme 7). It is impor-
tant to note that functionalized arylmethylzinc reagents
Keywords: cross-coupling · homogeneous catalysis · iron ·
synthetic methods · zinc
.
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Scheme 7. Iron-catalyzed oxidative heterocoupling with functionalized
ArZnMe.
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necessary. Nevertheless, satisfactory yields were obtained.
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À
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Scheme 8. Iron-catalyzed oxidative heterocoupling with functionalized
ArZnMe.
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Communications
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