Iron-catalysed, hydride-mediated reductive cross-coupling of vinyl halides and Grignard reagents

Article abstract of DOI:10.1039/c1cc14622j

An iron-catalysed, hydride-mediated reductive cross-coupling reaction has been developed for the preparation of alkanes. Using a bench-stable iron(ii) pre-catalyst, reductive cross-coupling of vinyl iodides, bromides and chlorides with aryl- and alkyl Grignard reagents successfully gave the products of formal sp³-sp³ cross-coupling reactions.

Full text of DOI:10.1039/c1cc14622j

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COMMUNICATION
Iron-catalysed, hydride-mediated reductive cross-coupling of vinyl halides
and Grignard reagentswz
Bryden A. F. Le Bailly, Mark D. Greenhalgh and Stephen P. Thomas*
Received 28th July 2011, Accepted 14th October 2011
DOI: 10.1039/c1cc14622j
An iron-catalysed, hydride-mediated reductive cross-coupling
reaction has been developed for the preparation of alkanes.
Using a bench-stable iron(II) pre-catalyst, reductive cross-coupling
of vinyl iodides, bromides and chlorides with aryl- and alkyl
Grignard reagents successfully gave the products of formal
sp3–sp3 cross-coupling reactions.
Fig. 1 Iron-catalysed, hydride-mediated reductive cross-coupling.
also been used to reduce alkenes, a,b-unsaturated ketones and
esters.
Metal-catalysed cross-coupling reactions have become ubiquitous
We recently developed an iron-catalysed, hydride-mediated
in synthetic chemistry with palladium- and nickel-catalysed
reduction of alkenes using sodium triethylborohydride.15
Examination of the postulated catalytic cycles of the iron-
catalysed hydrogenation11 and cross-coupling16 reactions
reveal common low-valent iron species. We therefore sought
to combine both of these reactions into one transformation,
catalysed by a single, bench stable, iron pre-catalyst. Reductive
cross-coupling is proposed to proceed by iron-catalysed cross-
coupling of the vinyl halide and Grignard reagent to give an
alkene 2. This alkene is then reduced in situ by an iron hydride
to the alkane 3 (Fig. 1). The iron hydride is generated by the
reaction of the iron salt with a stoichiometric hydride reagent.
This transformation gives the product of an sp3–sp3 cross-coupling
without the problems associated with these reactions.1 Further-
more, as the Grignard reagent needed for cross-coupling
generates a low-valent iron species in situ, we will be able to
use bench-stable iron(II) pre-catalysts.
reactions used routinely in both academia and industry.1
However, preceding the seminal discoveries of Heck2 and
Kumada,3 Kharasch4 and, later, Kochi reported the iron-
catalysed cross-coupling of vinyl bromides and Grignard
reagents.5 Iron-catalysed cross-coupling reactions have since
been developed into a powerful method for the formation of
carbon–carbon6 and carbon–heteroatom bonds.7
The last decade has seen a significant increase in the number
of transformations achieved using iron catalysts.8 The iron-
catalysed reduction of carbonyl groups by hydrosilylation,
transfer-hydrogenation and hydrogenation are now well
developed, with turnover frequencies equal to those of the
best ruthenium-based catalysts and good enantioselectivities
have been achieved for the reduction of ketones and imines.9
However, the reduction of olefins is only now being realised
without the need for forcing reaction conditions. Chirik has
developed a series of iron(0) complexes, based on the polymeri-
sation catalysts of Gibson and Brookhart,10 which catalyse the
hydrogenation of functionalised and unfunctionalised alkenes
at low hydrogen pressure and with excellent activity.11 de Vries
has used iron nanoparticles as the catalyst for the hydrogenation
of alkenes and alkynes.12 However, both of these powerful
methods use air- and moisture-sensitive iron species which
require synthesis prior to the hydrogenation reaction. Iron
porphyrin complexes and sodium borohydride,13 and iron
chloride in conjunction with lithium aluminium hydride14 have
In order to develop the reductive cross-coupling we chose
commercially available b-bromostyrene 4 and ethyl magnesium
chloride as model coupling partners and iron(II) chloride as the
iron source (Table 1). Sodium triethylborohydride was initially
used as the hydride source and N-methyl pyrrolidinone (NMP)
7 as a stabilising ligand due to the success we had with these
reagents for the isolated reduction of alkenes.15 Using 10 mol%
iron(II) chloride, 110 mol% NMP and 10 equivalents of
NaHBEt3 gave the reduced cross-coupled alkane 5 in only
9% conversion and the cross-coupled alkene 6 in 53% (entry 1).
This indicated that although cross-coupling was successful, the
alkene was not being reduced under these conditions. We assumed
that either the iron catalyst was not capable of mediating the
hydrogenation or was degrading before hydrogenation could
occur. To extend catalyst lifetime we screened multidentate
ligands and found that the tetradentate dipyridyldiimino
ligand 9 gave 56% conversion to the alkane 5 and 44% alkene
6 (entries 2 and 3). This showed that complete cross-coupling
was achieved and the hydrogenation step now needed
School of Chemistry, University of Bristol, Cantock’s Close, Bristol,
BS8 1TS. E-mail: stephen.thomas@bristol.ac.uk;
Fax: +44(0)117 925 1295
w This article is part of the ChemComm ‘Emerging Investigators 2012’
themed issue.
z Electronic supplementary information (ESI) available: Full experi-
mental procedures and analytical data are available. See DOI:
10.1039/c1cc14622j
c
1580 Chem. Commun., 2012, 48, 1580–1582
This journal is The Royal Society of Chemistry 2012

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improvement. Thus, we screened a number of hydride sources
(entries 4–12). Variation of the cation of the hydride source
showed that KHBsBu3(K-Selectride) (entry 6) gave a similar
conversion as NaHBEt3, but the use of reagents with a lithium
counter ion gave the best conversions (entries 7–9). LiHBEt3
gave a 20% increase in alkane 5 (entry 7), compared to
NaHBEt3, and lithium N,N-dimethylaminoborohydride17
gave quantitative conversion to the alkane 5 (entry 8). It should
be noted that even in the absence of ligand the reductive cross-
coupling proceeded, but only 61% of the alkane 5 and 24%
alkene 6 were observed (Table 1, entry 9). Without iron(II)
chloride no cross-coupling or reduction products were observed.
To test if the reductive cross-coupling was catalysed by an iron
species or a trace metal impurity,18 the reaction was carried
out with added Cu, Ni and Co salts and with these metals in
the absence of iron. No reductive cross-coupling was observed
using Cu, Ni or Co salts alone and the yield of the reaction was
not increased when these salts were added to the standard
reaction conditions.19
the formation of the key low-valent iron species is now not
possible. However, methylmagnesium chloride gave moderate
conversion to the alkane 11a (entry 1). Presumably an anionic
ferrate complex16 is the catalytically active iron species when
using this Grignard reagent. Using allylmagnesium chloride
introduced a second alkene to the reaction and this was also
reduced under the reaction conditions to give the fully saturated
alkane 11e, albeit in low yield (entry 6).
We next turned our attention to the effect of varying the
halide substituent of the vinyl halide (entries 7–12). Using the
elegant methodology of Charette20 we prepared a series of
aryl-vinyl halides bearing differing aryl and vinyl functionality.
b-Iodo- and b-bromo-4-methylstyrene gave equal conversions
to the alkane 11f, but b-chloro-4-methylstyrene gave 13% of
the alkane 11f and 46% of the alkene (entries 7–9). Electron-
deficient aryl-vinyl halides showed no such dependence on the
vinyl halide substituent. Both b-chloro- and b-bromo-4-chloro-
styrene gave similar conversion to the alkane 5 (entries 10–11).
However, proto-dehalogenation of the aromatic ring was
observed in both cases, possibly suggesting a low-valent iron
catalyst.21 Finally, we tested the electron-rich b-bromo-3,5-
dimethoxystyrene and this gave comparable conversion to that
observed when using the electron-neutral aryl-vinyl halides
(entry 12).
Table 1 Optimisation of the iron-catalysed, hydride-mediated reductive
cross-couplinga
Table 2 Scope and limitation of the iron-catalysed, hydride-mediated
reductive cross-couplinga
Conversion (%)b
Conversion (%)b
R1
X
R2
Alkane
11
Alkane 5
Alkene 6
Entry
Entry
Hydride
Ligand
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Br
Br
Br
Br
Br
Br
I
Br
Cl
Cl
Br
Br
Me
Et
53
99 (84c)
87
11a
5
1
2
3
4
5
6
7
8
NaHBEt3
NaHBEt3
NaHBEt3
NaHB(OAc)3
LiHAl(OtBu)3
KHBsBu3
LiHBEt3
LiH3BNMe2
LiH3BNMe2
NaBH4
NMP 7c
DPB 8
9
2
53
91
44
78
73
44
27
—
24
93
94
87
iPr
tBu
Ph
Allyl
Et
11b
11c
11d
11ef
11f
11f
11f
5
9
9
9
9
9
9
—
9
9
9
56
—
25
55
73
99
61
—
—
—
37d
41e
35
92 (87c)
91
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-Cl-Ph
4-Cl-Ph
3,5-MeO-Ph
Et
Et
Et
Et
9
13g
60
66
81
9
10
11
12
10
11
12
5
11g
LiAlH4
HSiEt3
Et
a
a
Conditions: 1 mmol 10, 10 mol% [9FeCl2], THF (0.1 M), ꢀ20 1C, (i)
Conditions: 1 mmol 4, 10 mol% FeCl2, 10 mol% ligand, THF (0.1 M),
ꢀ20 1C, (i) 1.4 eq. EtMgCl (2M in THF), 15 min, (ii) 10 eq. hydride,
1.4 eq. R2MgCl (2M in THF), 15 min, (ii) 10 eq. [LiH3BNMe2] (1.7 M
b
in THF), warm to rt, 16 h. Conversion measured by GC-MS of the crude
b
warm to rt, 16 h. Conversion measured by GC-MS of the crude
c
reaction mixture by comparison to authentic samples. 110 mol% NMP.
c
reaction mixture by comparison to authentic samples. Isolated yield.
d
e
f
61% 1,4-diphenylbutane. 40% biphenyl. Complete reduction of R2
observed in the reaction, product 11e R2 = n-propyl. 46% alkene.
g
Having developed optimised reaction conditions we investigated
the scope and limitations of the reductive cross-coupling
(Table 2). We began by using b-bromostyrene and a range of
alkyl Grignard reagents (entries 1–6). Ethyl- and iso-propyl-
magnesium chloride both gave excellent conversions to the
alkanes (entries 2 and 3). tert-Butyl- and phenylmagnesium
chloride gave a moderate conversion to the alkane, but no
alkene was observed (entries 4–5). Using Grignard reagents
without a b-hydrogen was expected to give poor conversion as
At this point we were unsure why the low alkane conversions
were not accompanied by significant amounts of the inter-
mediary alkenes. In the cases with low conversion to the
alkane 11, careful examination of the crude reaction mixtures
revealed that the vinyl halide 10 was undergoing reductive
homo-coupling to give the 1,4-diarylbutane 13, presumably via
the 1,4-diarylbutadiene 12 (Fig. 2).
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1580–1582 1581

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5 M. Tamura and J. K. Kochi, J. Am. Chem. Soc., 1971, 93, 1487;
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Fig. 2 Proposed homocoupling of vinyl halides.
In order to address this we examined the time between
Grignard and hydride addition, the time over which the
Grignard reagent was added, and the initial temperature of
the reaction. Under our standard reaction conditions using
iPrMgCl, variation of all these parameters led to very similar
results with no increase in the conversion to the target alkane.
We therefore suspected the hydride reagent was causing the
low conversions. Carrying out the reaction in the absence of
Grignard reagent confirmed this. Reaction of b-bromostyrene
4 with 10 mol% [9FeCl2] and 10 equivalents of lithium N,
N-dimethylaminoborohydride gave 74% conversion to the
fully reduced homo-coupled product, 1,4-diphenylbutane 14,
and 26% of the mono-reduced homo-coupled alkene 15
(Scheme 1). Presumably when cross-coupling is slow, for
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t
example with BuMgCl, the rate of hydride-mediated homo-
9 For reviews see: K. Junge, K. Schroder and M. Beller, Chem.
¨
coupling becomes competitive with the rate of Grignard-
mediated cross-coupling. Thus, on addition of the hydride
reagent any remaining vinyl halide 10 can either undergo
reductive homo-coupling to give the diarylbutane 13 or reductive
cross-coupling to alkane 11. Further studies are ongoing to
overcome and exploit this problem.
Commun., 2011, 47, 4849; P. J. Chirik, in Catalysis without Precious
Metals, ed. R. M. Bullock, Wiley-VCH, Weinheim, Germany,
2010, pp. 83–110; For selected recent examples see: R. Langer,
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10 G. J. P. Britovsek, V. C. Gibson, B. S. Kimberley, P. J. Maddox,
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Scheme 1 Iron-catalysed, hydride-mediated homo-coupling of
b-bromostyrene.
11 S. C. Bart, E. Lobkovsky and P. J. Chirik, J. Am. Chem. Soc.,
2004, 126, 13794; S. C. Bart, E. J. Hawrelak, E. Lobkovsky and
P. J. Chirik, Organometallics, 2005, 24, 5518; R. J. Trovitch,
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In summary, we have developed an iron-catalysed, hydride-
mediated reductive cross-coupling reaction for the preparation
of alkanes from vinyl halides and Grignard reagents using a
simple, bench-stable iron(II) pre-catalyst and commercially
available reagents. This transformation gives the product of
a formal sp3–sp3 cross-coupling reaction by the in situ
reduction of an intermediate alkene to the alkane. The scope
and limitations of this reaction have been tested and moderate
to excellent conversions have been observed in the reductive
cross-coupling of vinyl bromides, iodides and chlorides with
aryl and alkyl Grignard reagents.
12 P.-H. Phua, L. LeFort, J. A. F. Boogers, M. Tristany and J. G. de
Vries, Chem. Commun., 2009, 3747; C. Rangheard, C. de J.
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We thank Prof. V. K. Aggarwal for his support and
generosity. S. P. T. thanks N. C. O. Tomkinson, S. Warren
and D. J. Fox for continued support. M. D. G. thanks the
Bristol Chemical Synthesis Doctoral Training Centre, funded
by EPSRC (EP/G036764/1) for a studentship
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Notes and references
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c
1582 Chem. Commun., 2012, 48, 1580–1582
This journal is The Royal Society of Chemistry 2012