Simple iron-amine catalysts for the cross-coupling of aryl Grignards with alkyl halides bearing β-hydrogens

Article abstract of DOI:10.1039/b507133j

Mixtures of iron(III) chloride and appropriate amine ligands are active catalysts for the coupling of aryl Grignard reagents with primary and secondary alkyl halide substrates bearing β-hydrogens, under mild and simple reaction conditions. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b507133j

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COMMUNICATION
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Simple iron-amine catalysts for the cross-coupling of aryl Grignards
with alkyl halides bearing b-hydrogens
Robin B. Bedford,*a Duncan W. Bruce,b Robert M. Frostc and Michael Hirdd
Received (in Cambridge, UK) 20th May 2005, Accepted 23rd June 2005
First published as an Advance Article on the web 22nd July 2005
DOI: 10.1039/b507133j
a greater than stoichiometric amount of amine is required, which is
added with the Grignard reagent. Secondly, for optimal perfor-
mance the Grignard/amine mixture must be added slowly via the
use of a syringe pump and thirdly, typically, the reactions must be
cooled to 0 uC or lower. If it were possible to circumvent these
limitations then this would represent a very powerful technique,
due to the simplicity of the catalyst systems. We find that these
problems are indeed surmountable: amines can be used in catalytic
quantities; the reactions can be performed at elevated temperatures
and there is no requirement for slow addition of the Grignard. The
preliminary findings of this study are reported below.
Mixtures of iron(III) chloride and appropriate amine ligands are
active catalysts for the coupling of aryl Grignard reagents with
primary and secondary alkyl halide substrates bearing b-hydro-
gens, under mild and simple reaction conditions.
The transition metal catalysed Grignard cross-coupling reaction is
a powerful tool for the formation of C–C bonds.1 The use of
primary, and particularly, secondary alkyl halides as substrates
poses problems in that they tend to be less reactive than aryl
halides and the intermediate alkyl complexes formed tend to be
prone to rapid b-elimination reactions generating alkene products.2
Recent studies show that the problem of b-elimination is
surmountable.3 For instance Ni and Pd complexes have been
shown to catalyse the coupling of primary alkyl halide substrates
with appropriate nucleophilic coupling partners,3 while Co,4 Ni5
and Fe6,7 catalysts have all recently shown activity in coupling
reactions of primary and secondary alkyl substrates, typically
without large amounts of b-eliminated by-product formation.
Of particular note are recent reports of the use of iron(III)
complexes as pre-catalysts in the cross-coupling of both primary
and secondary alkyl halides with aryl Grignard reagents. Nagano
and Hayashi showed that [Fe(acac)3] can be used to good effect,6
while Martin and Fu¨rstner showed the ferrate complex
[Li(tmeda)2][Fe(C2H4)4] to be effective in the coupling of a large
range of alkyl halides with diverse functionality.8 We found that
simple iron–salen complexes can also be exploited.9 Nakamura
and co-workers demonstrated that iron(III) chloride can be
employed in the presence of stoichiometric amounts of appropriate
amines, particularly TMEDA, provided the Grignard is added
slowly via a syringe pump.7 While this latter method is particularly
attractive, due to the simplicity of the catalyst and the excellent
results obtained, it currently suffers from three limitations. Firstly,
For the initial screening of catalyst performance, we chose the
reaction outlined in eqn. (1) as a typical example of aryl Grignard–
secondary alkyl coupling.{ Fig. 1 shows the conversion to coupled
(1)
aSchool of Chemistry, University of Bristol, Cantock’s Close, Bristol,
UKBS81TS. E-mail:r.bedford@bristol.ac.uk;Fax:+44(0)1179251295
bDepartment of Chemistry, University of York, Heslington, York, UK
YO10 5DD
cDepartment of Chemistry, University of Exeter, Exeter, UK EX4 4QD
dKingston Chemicals, University of Hull, Cottingham Road, Kingston
upon Hull, UK HU6 7RX
Fig. 1 Screening of activity of Fe–amine catalysts in the coupling of
4-tolylMgBr with cyclohexyl bromide.{
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product 2 along with the formation of the elimination product –
cyclohexene (3), the hydrodehalogenated product – cyclohexane
(4), and the two homo-coupled products dicyclohexyl (5) and
bitolyl (6) with a range of amine–Fe catalysts. Surprisingly, we
found that, under these conditions, even FeCl3 in the absence of
added amine shows some activity – 39% (catalyst entry N). This is
in contrast with the findings of Nakamura and co-workers who
found very little hetero-coupling versus large amounts of elimina-
tion product under their conditions.7 The addition of amine
ligands in catalytic loadings leads to substantial improvement in
activity.
(entries C–E) proved effective; by contrast Nakamura and co-
workers found this ligand to be very poor under their conditions.7
There does not appear to be a general trend in performance on the
ratio of Fe to N-donors across the series, rather any effect seems to
be ligand-specific.
The pre-formed iron(III) 1,3,5-trimethylhexahydro-1,3,5-triazine
complex 710 gives a healthy 86% conversion to the hetero-coupled
product 2 under the same conditions as in Fig. 1. By contrast its
chromium analogue 810 gives none of the desired product.
As can be seen, most of the amines tested show good to excellent
conversions to coupled product 2 with minimum levels of
contamination by 3 and 4. The best activities tend to be obtained
with either mono- or bidentate tertiary amines, with chelating
primary and secondary bis-amine ligands typically showing lower
performance. Interestingly, the use of triethylamine as the ligand
The three best ligands – triethylamine, DABCO and TMEDA –
were then screened against a range of substrates and the results
are summarised in Table 1.{ In all cases the Fe : N ratio was kept
at 1 : 2.
Table 1 Cross-coupling of alkyl with aryl Grignard reagents
Conversion (%)a with catalyst system
Entry ArMgBr
1
Alkyl halide
Product
FeCl3 + 2 NEt3 FeCl3 + TMEDA FeCl3 + DABCO
75
79
69
90
79
60
100
2
3
88
74
4
5
84
75
59
62
62
70
6
7
0
0
0
85
75
93
(cis : trans ratio
1 : 1.9)
(cis : trans ratio (cis : trans ratio
1 : 1.5) 1 : 1.8)
(cis : trans ratio 1 : 3.2)
8
9
66
74
49
44
40
61
10
octyl–Br
70
63
62
a
Conversion to product determined by 1H NMR spectroscopy (mesitylene internal standard).
4162 | Chem. Commun., 2005, 4161–4163
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As can be seen, in contrast with the results obtained by
Nakamura and co-workers under their conditions,7 the TMEDA
system fared least well in nearly all reactions. With cyclohexyl
substrates, the best catalyst proved to be that based on
FeCl3/DABCO in nearly all cases (entries 1–3 and 7), except in
the reaction of the hindered aryl Grignard, 2-tolyl magnesium
bromide, with bromocyclohexane. In this instance the best catalyst
was that based on FeCl3/NEt3. None of the catalysts tested were
able to couple the hindered substrate 2-meta-xylylmagnesium
bromide (entry 6). In the coupling of 4-tolyl magnesium bromide
with 4-methylcyclohexyl bromide (entry 7) the DABCO/FeCl3
catalyst system gives not only the highest conversion to coupled
product but also the greatest trans-selectivity. The variation in
cis : trans ratio compared to that of the starting alkyl bromide and
the difference in selectivity with varying catalysts tend to argue
against a simple oxidative addition of the alkyl halide to the metal
centre during the catalytic cycle, a point that will be discussed
further later. When either primary alkyl halides or open-chain
secondary alkyl halides are used, the best catalyst system tested
proves to be FeCl3/NEt3 (entries 8–10).
(bromomethyl)cyclopropane, 9, (Scheme 1). If an oxidative
addition pathway is operative then it would be expected that the
simple coupled product 10 would form.12 However this is not the
case, instead the ring-opened product 4-phenylbutene, 11, is
obtained, lending support to a radical pathway.13 Further evidence
for an alkyl radical intermediate is provided by the reaction of
phenylmagnesium bromide with 6-bromohexene (Scheme 2); this
predominantly yields the ring-closed product 12 as well as the
simple coupled product 13.14
In summary, we have found that simple iron catalysts formed
in situ from FeCl3 and appropriate amines are active catalysts for
the coupling of primary and secondary alkyl halides with aryl
Grignard reagents without the need for excess amine, slow
addition of the Grignard or low reaction temperatures. Research
is ongoing to try to establish the nature of the true active catalyst
species.
We thank the EPSRC for the provision of an Advanced
Research Fellowship for RBB, the COMIT Faraday Partnership,
Kingston Chemicals and EPSRC for support to RMF and
Professor John Goodby for helpful discussions.
With regards to a possible mechanism, Nagano and Hayashi
suggest that Fe-based couplings of alkyl halides with aryl
Grignards may proceed via oxidative addition of the alkyl halide
to a reduced iron complex,6 that is to say a two-electron redox
pathway is involved. By contrast Nakamura and co-workers
invoke a radical pathway in which the reduced iron catalyst enters
a one-electron redox pathway and an alkyl radical is formed from
the alkyl halide.7 It was proposed that any alkyl radical formed in
such a pathway may not be free, but rather remains ‘associated’
with the metal centre.11 Their observation that an enantio-pure
secondary alkyl bromide is converted to a racemic mixture of
coupled product is strongly supportive of a radical pathway.
In order to probe further whether the mechanism proceeds via a
classical oxidative addition manifold or by a radical pathway, we
investigated the coupling of phenylmagnesium bromide with
Notes and references
{ The appropriate amount of amine in CH2Cl2 (2 ml) was added to
anhydrous FeCl3 (0.1 mmol) and then after standing (2 min) the solvent
was removed in vacuo. Et2O (3 ml) was added and the solution was stirred
(y 2 min). CyBr (1.0 mmol) was added, the solution stirred for 5 minutes,
then heated to reflux temperature (external temperature 45 uC; reaction
temperature y 36–38 uC) and 4-MeC6H4MgBr (1.0 M solution in Et2O,
2.0 ml) was added in one portion. The reaction was then heated for 30 min,
quenched with H2O (5 ml), extracted with CH2Cl2 (3 6 5 ml) and dried
(MgSO4). Mesitylene (internal standard, 0.1439 M in CH2Cl2, 1.00 ml) was
added and the conversion to products 2–6 was determined by GC analysis.
{ Reactions performed as above with appropriate alkyl halide (2.0 mmol),
ArMgBr (4.0 mmol) and catalyst (5 mol% Fe). Reactions were quenched
(H2O, 5 ml), extracted with CH2Cl2 (3 6 5 ml) and dried (MgSO4).
Mesitylene (internal standard, 0.667 M in CH2Cl2, 1.00 ml) was added, an
aliquot (2 ml) was removed from which the solvent was removed at room
temperature under reduced pressure. The residue was dissolved in CDCl3
(y 0.7 ml) and the conversion to coupled product was determined by 1H
NMR spectroscopy.
1 Review: Metal-catalyzed cross-coupling reactions, F. Diederich and P. J.
Stang, Eds., Wiley-VCH, Weinheim, 1998.
2 M. R. Netherton and G. C. Fu, Adv. Synth. Catal., 2004, 346, 1525.
3 Reviews: (a) A. C. Frisch and M. Beller, Angew. Chem., Int. Ed., 2005,
44, 674; (b) D. J. Ca´rdenas, Angew. Chem., Int. Ed., 2003, 42, 384.
4 T. Tsuji, H. Yorimitsu and K. Oshima, Angew. Chem., Int. Ed., 2002,
41, 4137.
5 J. Zhou and G. C. Fu, J. Am. Chem. Soc., 2004, 126, 1340.
6 T. Nagano and T. Hayashi, Org. Lett., 2004, 6, 1297.
7 M. Nakamura, K. Matsuo, S. Ito and E. Nakamura, J. Am. Chem.
Soc., 2004, 126, 3686.
8 R. Martin and A. Fu¨rstner, Angew. Chem., Int. Ed., 2004, 43, 3955.
9 R. B. Bedford, D. W. Bruce, R. M. Frost, J. W. Goodby and M. Hird,
Chem. Commun., 2004, 2822.
Scheme 1 Conditions: PhMgBr (4.0 mmol), 9 (2.0 mmol), cat 5 FeCl3/2
Et3N (5 mol%), Et2O/THF (3 : 2), 45 uC, 30 min. Yield determined by 1H
NMR spectroscopy.
10 R. D. Ko¨hn and G. Kociok-Ko¨hn, Angew. Chem., Int. Ed. Engl., 1994,
33, 1877.
11 For leading refs. see: M. Wakioka, K.-Y. Baek, T. Ando, M. Kamigaito
and M. Sawamoto, Macromolecules, 2002, 35, 330.
12 J. Terao, H. Watanabe, A. Ikumi, H. Kuniyasu and N. Kambe, J. Am.
Chem. Soc., 2002, 124, 4222.
13 For the use of (bromomethyl)cyclopropane as a probe of radical
pathways in coupling reactions see: Y. Ikeda, T. Nakamura,
H. Yorimitsu and K. Oshima, J. Am. Chem. Soc., 2002, 124, 6514
and references therein.
14 Interestingly, Nakamura and co-workers found that with greater than
stoichiometric amounts of amine additive, 13 predominates with little or
no 12 observed, depending on precise conditions. See ref. 7.
Scheme 2 Conditions: PhMgBr (4.0 mmol), 6-bromohexene (2.0 mmol),
cat 5 FeCl3/2 Et3N (5 mol%), Et2O/THF (3 : 2), 45 uC, 30 min. Yields
determined by H NMR spectroscopy.
1
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Chem. Commun., 2005, 4161–4163 | 4163