Iron nanoparticles in the coupling of alkyl halides with aryl Grignard reagents

Article abstract of DOI:10.1039/b601014h

Iron nanoparticles, either formed in situ stabilized by 1,6-bis(diphenylphosphino)hexane or polyethylene glycol (PEG), or preformed stabilized by PEG, are excellent catalysts for the cross-coupling of aryl Grignard reagents with primary and secondary alkyl halides bearing β-hydrogens and they also prove effective in a tandem cyclization/cross- coupling reaction. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b601014h

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Iron nanoparticles in the coupling of alkyl halides with aryl Grignard
reagents{
Robin B. Bedford,*a Michael Betham,a Duncan W. Bruce,b Sean A. Davis,a Robert M. Frostc and
Michael Hirdd
Received (in Cambridge, UK) 20th January 2006, Accepted 17th February 2006
First published as an Advance Article on the web 24th February 2006
DOI: 10.1039/b601014h
Iron nanoparticles, either formed in situ stabilized by 1,6-
bis(diphenylphosphino)hexane or polyethylene glycol (PEG),
or preformed stabilized by PEG, are excellent catalysts for the
cross-coupling of aryl Grignard reagents with primary and
secondary alkyl halides bearing b-hydrogens and they also
prove effective in a tandem cyclization/cross-coupling reaction.
The coupling of Grignard reagents with alkyl halide substrates
bearing b-hydrogens can prove problematic. This is because the
intermediate metal–alkyl complexes formed are prone to rapid
competitive b-elimination reactions that generate unwanted alkenic
by-products. Recent studies show that the issue of b-elimination is
surmountable in a range of coupling reactions.1 Building on
Kochi’s seminal observations that iron-based catalysts can be
employed in cross-coupling reactions of vinyl halides,2 several
notable reports have recently appeared on the use of iron pre-
catalysts in the cross-coupling of both primary and secondary alkyl
halides with aryl Grignard reagents (Scheme 1).
Nagano and Hayashi showed that [Fe(acac)3] can be used to
good effect,3 while Martin and Fu¨rstner demonstrated that the
ferrate complex [Li(tmeda)2][Fe(C2H4)4] performs well in the
coupling of a range of substrates with diverse functionality.4 We
have shown that certain iron-salen based systems are also active.5
Scheme 2 Coupling of 4-methylcyclohexyl bromide with 4-tolylmagne-
sium bromide catalysed by Fe-imine-based species.
Particularly simple, yet highly active catalyst systems based on
FeCl3 and either stoichiometric or catalytic quantities of amine
additives have been reported.6,7 While Nakamura and co-workers
reactions are allowed to turn black. Furthermore we now find that
the four imine-based iron catalysts shown in Scheme 2 are also
took precautions in order to prevent their reaction mixtures
active; again the reactions turn black immediately on addition of
the Grignard reagent.9 The breadth of pre-catalysts structures that
turning black (low temperature, slow addition of ArMgX,
stoichiometric amine additive),6 we found that these measures
are not always necessary for good activity, indeed a far larger
range of pre-catalysts, not only with amine7 but also phosphine,
arsine, phosphite and carbene ligands,8 can be employed if the
Scheme 1
aSchool of Chemistry, University of Bristol, Cantock’s Close, Bristol,
UK BS8 1TS. E-mail: r.bedford@bristol.ac.uk
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
{ Electronic supplementary information (ESI) available: Experimental
data, TEM images, EDX analyses. See DOI: 10.1039/b601014h
Fig. 1 TEM image of the mixture obtained on reacting FeCl3–dpph
with 2.
1398 | Chem. Commun., 2006, 1398–1400
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Table 1 Coupling of aryl Grignard reagents with alkyl halides catalysed by in situ generated Fe–PEG catalysta
Entry
ArMgX
AlkX
Product
PEG MW
PEG/Feb
Conv., %c
1
2
3
4
5
6
7
8
9
14000
100
10
2.5
1
0.1
1
0
0
80
94d,e, (78)f
67
79
63
79 (r.t.)e
77
35000
2000
14000
2.5
10
11
12
13
82e
1
78e
79e
2
1
91d,e,h
14
15
78d,e
72d,e,h
16
30d,e
17
18
19
20
2
91d,e,k
81d,e
91d,e
21
Br–noctyl
85d,e, (80)f
a
Conditions: RX (1.0 mmol), ArMgBr (1 M, Et2O, 2.0 mmol), FeCl3 (0.05 mmol), Et2O (3 ml), 45 uC (external temp.; internal y35–38 uC),
0.5 h. Based on PEG monomer. Conv. to coupled product determined by 1H NMR (mesitylene internal standard). Pre-dried PEG
(toluene azeotrope). Average of two runs. Isolated yield. 0.5 M in THF. Hg (100–150 eq.) added. 1 M in THF. 1 M in THF. trans :
cis 5 70 : 30.
b
c
d
e
f
g
h
i
j
k
prove active led us to wonder whether there was in fact a common
catalytic species in all these cases; the black colouration suggested
that this may be nanoparticulate iron.10
a simpler stabilizing additive, namely polyethylene glycol (PEG).
We were delighted to find that this indeed proves to be the case;
Table 1 summarizes the catalytic data obtained in a brief survey
with this system.{
As can be seen, the best activity is obtained with PEG of Mw
14,000 g mol21 and an Fe-to-monomer ratio of between 1 : 1 and
1 : 2.5. Higher activity is obtained if the PEG is pre-dried. Slightly
better performance is seen at reflux temperature (y35–38 uC) than
at room temperature. Both cyclohexyl iodide and chloride are
coupled equally as effectively as the bromide (compare entries 3, 9
and 10), while increasing the bulk of the ArMgBr is deleterious to
the reaction with no activity observed using 2,6-Me2C6H3MgBr.
As far as we are aware there are no reports of the iron-catalyzed
coupling of such hindered, di-ortho-substituted aryl Grignard
In order to test this hypothesis we subjected the reaction
mixture obtained in the coupling of cyclohexyl bromide, 1,
with 4-MeC6H4MgBr, 2, catalyzed by FeCl3–dpph to TEM
(Fig. S1).{11 This shows fairly small (typically 5–12 nm) iron
nanoparticles associated with larger particles of MgX2.12,13 Similar
iron nanoparticles, typically in the range of 4–9 nm and associated
with larger MgX2 particles, are obtained on the reaction of an
FeCl3–dpph mixture with 2 in the absence of alkyl halide (Fig. 1),
indicating that the Grignard reagent acts as the reductant.
The catalytically active nanoparticles are presumably stabilized
by the phosphine ligand, prompting us to see whether we could use
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We thank the EPSRC (Advanced Research Fellowship to RBB,
PDRA to MB), the COMIT Faraday Partnership, Kingston
Chemicals and EPSRC for support for RMF (studentship).
Notes and references
{ See electronic supporting information for details.
Scheme 3
reagents with secondary alkyl halides.14 Primary and open chain
secondary alkyl halides can also be coupled effectively. TEM
analysis of a sample taken from the coupling of 1 with 2 again
shows iron nanoparticles.{ Interestingly, the addition of a large
excess of Hg does not prevent catalysis (entries 13 and 15).
Encouraged by the activity of the in situ-reduced FeCl3–PEG
system, we wondered if we could produce pre-formed iron
nanoparticles that function as equally active catalysts. Treatment
of an ether solution of FeCl3 and PEG with 5 equiv. of 2 gives a
black suspension, 3,15 which shows only a partial settling out of
some black precipitate over several days. TEM analysis of 3 shows
iron nanoparticles with a typical size range of about 7–13 nm in an
MgX2 matrix.{ Suspension 3 is air sensitive, turning yellow-brown
within minutes of exposure to air. GC analysis of a water-
quenched sample of 3 indicates the presence of 1.5 equiv. of
4,49-bitolyl per Fe, formed on the reduction of the FeCl3; exactly
consistent with the reduction of Fe(III) to Fe(0). The use of BuLi
instead of 2 gives a suspension 4 from which LiCl settles out within
a few hours.16
1 For reviews see: (a) A. C. Frisch and M. Beller, Angew. Chem., Int. Ed.,
2005, 44, 674; (b) M. R. Netherton and G. C. Fu, Adv. Synth. Catal.,
2004, 346, 1525; (c) D. J. Ca´rdenas, Angew. Chem., Int. Ed., 2003, 42,
384; (d) T.-Y. Luh, M.-K. Leung and K.-T. Wong, Chem. Rev., 2000,
100, 3187.
2 Recent overview: J. K. Kochi, J. Organomet. Chem., 2002, 653, 11.
3 T. Nagano and T. Hayashi, Org. Lett., 2004, 6, 1297.
4 (a) R. Martin and A. Fu¨rstner, Angew. Chem., Int. Ed., 2004, 43, 3955;
(b) See also the structural characterisation, reactivity and catalytic
activity of an unusual iron ‘‘super ate’’ complex: A. Fu¨rstner, H. Krause
and C. W. Lehmann, Angew. Chem., Int. Ed., 2006, 45, 440.
5 R. B. Bedford, D. W. Bruce, R. M. Frost, J. W. Goodby and M. Hird,
Chem. Commun., 2004, 2822.
6 M. Nakamura, K. Matsuo, S. Ito and E. Nakamura, J. Am. Chem.
Soc., 2004, 126, 3686.
7 R. B. Bedford, D. W. Bruce, R. M. Frost and M. Hird, Chem.
Commun., 2005, 4161.
8 R. B. Bedford, M. Betham, D. W. Bruce, A. A. Danopoulos,
R. M. Frost and M. Hird, J. Org. Chem., 2006, 71, 1104.
9 For syntheses of pre-formed iron complexes see: (a) G. J. P. Britovsek,
M. Bruce, V. C. Gibson, B. S. Kimberley, P. J. Maddox, S. Mastroianni,
S. J. McTavish, C. Redshaw, G. A. Solan, S. Stro¨mberg, A. J. P. White
and D. J. Williams, J. Am. Chem. Soc., 1999, 121, 8728; (b)
R. K. O’Reilly, V. C. Gibson, A. J. P. White and D. J. Williams,
J. Am. Chem. Soc., 2003, 125, 8450.
10 Suspensions of iron nanoparticles are typically black, see, for example:
(a) Y. Koltypin, N. Perkas and A. Gedanken, J. Mater. Chem., 2004,
14, 2975; (b) L. Guo, Q. Huang, X.-Y. Li and S. Yang, Phys. Chem.
Chem. Phys., 2001, 3, 1661.
Suspension 3 shows very similar activity to the catalyst formed
in situ in the coupling of 1 with 2 (91%; compare with entry 4). The
use of 3 in the reaction of 2 with 4-MeC6H10Br gives the coupled
product (80%) with a trans-selectivity of 72% – very close to that
obtained with FeCl3–PEG (entry 18). Repeating the coupling of 1
with 2 catalyzed by samples of 3 aged for 1 and 15 days shows only
a moderate reduction in activity (70% and 71% conversion
respectively).17,18 In stark contrast with the activity shown by 3, 4
performs very poorly in the coupling of 1 with 2 (4%), possibly due
to the observed particle aggregation.19
11 dpph 5 1,6-bis(diphenylphosphino)hexane. This reaction gives 91%
conversion to 4-MeC6H4Cy, see ref. 8.
12 EDX analysis reveals the presence of Mg, Cl and Br.
13 No special precautions were taken to prevent oxidation of the iron
nanoparticles in the TEM analyses, so it is likely that the majority of the
iron is in the form of an amorphous oxide phase in all cases.
14 Hayashi and co-workers showed that the similarly sized 2,4,6-
Me3C6H2MgBr reacts with a primary alkyl halide, see ref. 3.
15 As in ref. 10b, powder XRD of a dried sample of 3 is inconclusive,
probably because the particles are small and amorphous.
16 TEM analysis of a sample of 4 shows much larger aggregates of more
polydisperse particles – see supporting information.
17 This decrease may correspond to some catalyst precipitation.
18 At this stage it is not possible to say whether the catalysis occurs at the
nanoparticle surface, or whether the nanoparticles act as a ‘reservoir’ for
soluble catalytic species as is probably the case when palladium
nanoparticles are used in coupling reactions. See for instance: A. H.
M. de Vries, J. M. C. A. Mulders, J. H. M. Mommers, H. J.
W. Henderickx and J. G. de Vries, Org. Lett., 2003, 5, 3285.
19 The MgX2 salts in 3 and catalyst systems formed in situ from FeCl3–
PEG may play a role in nanoparticle stabilization with respect to
aggregation beyond that played by the PEG, which may explain the low
catalytic activity of 4.
20 5 as a radical probe, see: Y. Ikeda, T. Nakamura, H. Yorimitsu and
K. Oshima, J. Am. Chem. Soc., 2002, 124, 6514 and references therein.
21 A simple oxidative addition pathway would give PhCH2-cyclo-C3H5.
See: J. Terao, H. Watanabe, A. Ikumi, H. Kuniyasu and N. Kambe,
J. Am. Chem. Soc., 2002, 124, 4222.
22 To the best of our knowledge, catalytic organic applications of iron
nanoparticles are limited to Fischer–Tropsch synthesis, simulation of
coal liquefaction, the hydrogenation of naphthalene, the hydroformyla-
tion of an alkene, denitrogenation of nitrogen compounds and the
degradation of trichloroethylene. For leading references see: Small, 2005,
1, 482.
As for the mechanism of coupling of AlkX with ArMgX
catalyzed by iron nanoparticles, we currently favour a radical
process4,6 rather than a ‘classical’ coupling mechanism.3 This
preference is based on the results of the reactions of PhMgBr with
5 and 6 catalyzed by 3, both of which give products expected from
a radical-based mechanism (Scheme 3). The former reaction yields
the ring-opened product 7 only,20,21 while the latter reaction
produces the ring-closed product 8 as the major species. The
formation of 8 is an example of a tandem radical ring-closing/
cross-coupling reaction; to the best of our knowledge the first
reported for a nanoparticulate iron catalyst.
In summary we have demonstrated that iron nanoparticles,
both pre-formed or formed in situ, are excellent catalysts for the
coupling of aryl Grignard reagents with alkyl halides. In addition,
the nanoparticles can be exploited for tandem ring-closing/cross-
coupling. To the best of our knowledge this is the first time that
iron nanoparticles have been used in any cross-coupling or related
reactions.22 The facile synthesis of the particles, their thermal
stability and their ease of handling make them highly attractive for
use in a wide range of catalytic reactions. We are currently
examining the full scope of this new catalyst paradigm and the
results from this study will be presented later.
1400 | Chem. Commun., 2006, 1398–1400
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