Room temperature hydrophosphination using a simple iron salen pre-catalyst

Article abstract of DOI:10.1039/c4cc06526c

Phosphines are fundamentally important to the fine chemicals, pharmaceutical and agrochemical industries. Reported is the first example of alkene hydrophosphination using a designed iron pre-catalyst which yields the anti-Markovnikov products in high yield at room temperature. The phosphine products are excellent pro-ligands for Fe-catalyzed Negishi cross-coupling. This journal is

Full text of DOI:10.1039/c4cc06526c

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Room temperature hydrophosphination using a
simple iron salen pre-catalyst†
Cite this: Chem. Commun., 2014,
50, 12109
K. J. Gallagher and R. L. Webster*
Received 31st July 2014,
Accepted 20th August 2014
DOI: 10.1039/c4cc06526c
www.rsc.org/chemcomm
Phosphines are fundamentally important to the fine chemicals,
pharmaceutical and agrochemical industries. Reported is the first
example of alkene hydrophosphination using a designed iron pre-
catalyst which yields the anti-Markovnikov products in high yield at
room temperature. The phosphine products are excellent pro-ligands
for Fe-catalyzed Negishi cross-coupling.
Scheme 1 Room temperature, anti-Markovnikov selective iron-catalyzed
hydrophosphination.
The synthesis of phosphorus-containing motifs is of fundamental
importance in terms of the preparation of ligands for use in
homogeneous catalysis,1 organocatalysis2 and as synthetic reagents
in their own right.3 Hydrophosphination (HP) offers the ideal P–C
bond-forming process: the potential to be a 100% atom economic
transformation with opportunities for regio- and stereocontrol,
where molecular complexity can be rapidly accessed from simple,
commercially available starting materials.4,5 Whilst Platinum Group
Metals (PGMs), early transition metals, lanthanides alkaline- and
rare-earth metals have all4 proved competent in catalyzing HP, it is
of note that the use of base metals in this transformation is
limited.6,7 With this in mind, and driven by the major global efforts
towards the development of sustainable chemical methodology, we
sought to address these challenges through the use of iron, an
appealing low cost, highly abundant, biocompatible and non-toxic
alternative to the PGMs. Remarkably, despite the intense activity
currently surrounding the development of iron catalysis, only simple
Fe(II)/(III) chloride salts have been reported for the HP of electron
deficient alkenes at a sub-stoichiometric loading of 0.3 eq.8 Catalyst
design presents a significant opportunity to tune the reactivity of
such systems, moving to lower catalyst loadings and room tempera-
ture; herein we report the use of a simple Fe(III) salen pre-catalyst
for HP. The reaction takes place at room temperature, with only
0.5 mol% catalyst loading and without the need for any additives
(Scheme 1). Furthermore, we extend this methodology beyond
simple synthesis by exploiting the products of HP as ligands in their
own right, an often overlooked facet of HP. Through this expressed
aim of developing this phosphine ligand motif for base metal
catalysis, we present some preliminary results in Fe-catalyzed
Negishi cross-coupling.
We initiated our research program into Fe-catalyzed HP by
synthesizing the simplest salen pro-ligand (1).9 Ligation to Fe(OAc)2
in EtOH gives a high yield of m-oxo-bis(N,N0-ethylenebis(salicyli-
deniminato)iron(III)) complex, 2a (Scheme 2), which is isolated
as the analytically pure compound in good yield (see ESI†).10,11
The Fe(II) analogue, 2b,12 is a highly air sensitive solid, requiring
preparation with rigorous air-sensitive handling techniques, how-
ever, we believe our route to 2b is the simplest definitive method for
its synthesis. Upon exposure of 2b to air, O2 activation takes place
and 2a is formed in modest yield.13
With Fe(III) (2a) and Fe(II) (2b) pre-catalysts in hand, we
began to investigate their use in HP. To our delight it was found
that 0.5 mol% of 2a catalyzes the reaction between styrene and
diphenylphosphine at room temperature to give a quantitative
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
E-mail: r.l.webster@bath.ac.uk
† Electronic supplementary information (ESI) available: All experimental and
analysis data. See DOI: 10.1039/c4cc06526c
Scheme 2 Synthesis of pre-catalysts 2a and 2b.
Chem. Commun., 2014, 50, 12109--12111 | 12109
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spectroscopic yield of the anti-Markovnikov (AM) product, 3a, Negishi cross-coupling.17 Surprisingly, very simple alkyl–aryl phos-
cleanly. The reaction proceeds similarly in a range of solvents phines such as 3a to 3l have never before been used as ligands in
(THF, CH2Cl2, MeCN) and also under solvent-free conditions; TM catalysis. Meanwhile Fe(II)-catalyzed Negishi cross-coupling is
however, considering both sustainability and ease of reaction an elegant transformation which demonstrates the potential of
monitoring, we proceeded with MeCN as the solvent of choice. base metal catalysis, allowing the synthesis of unsymmetrically
In the absence of any source of Fe only a trace amount of AM substituted diarylmethanes. To our delight these simple mono-
product is observed at RT in MeCN.
phosphines prove to be excellent pro-ligands for the cross-coupling
With mild conditions in hand we began to explore the substrate of diaryl zinc reagents and benzyl bromides (Scheme 3).18,19 To the
scope and limitations of this system. Pleasingly, a wide range of best of our knowledge this is the first reported use of these phos-
electron deficient alkenes including styrenes, halo-styrenes and phines in a catalytic transformation and furthermore the first report
acrylates all undergo HP to give the AM product in high yield of such a simple mono-phosphine facilitating a Negishi reaction
(Table 1). Heterocycles are well tolerated as evidenced by the of this type, with state-of-the-art examples often being undertaken
phosphine product 3n from 2-vinylpyridine (entry 14), which is with expensive bis-phosphines such as 1,2-bis(diphenylphosphino)-
known to be an important pro-ligand for carbonylation reactions benzene (dpbz). We also provide an example with 2-bromobenzyl
and Pd-catalyzed Suzuki–Miyaura cross-coupling.15 We believe the bromide, which cannot be accessed by traditional Pd-catalyzed
need for extended reaction times (72 h) is due to competing cross-coupling due to competing aryl–aryl bond formation. In
coordination of 3n to the Fe-center.
the absence of 3a only 16% diphenylmethane is observed from
The power of hydrophosphination is highlighted through the the reaction of benzyl bromide and diphenylzinc in the presence
facile synthesis of phosphinoester products 3o and 3p (entries 15 of 5 mol% FeCl2.
and 16). The phosphinoester core is a key component in the
We have initiated some preliminary mechanistic studies to
synthesis of diazo compounds for use in chemical biology. This further our understanding of this particular HP catalytic system.
P–C bond formation requires four sequential steps when using Unactivated substrates (i.e. 1-hexene, allylbenzene) only show trace
traditional methods.16 However, with HP the same key P–C bond amounts of the desired product. The reaction mediated by 2a does
forming process is undertaken in one step at room temperature in not appear to be radical catalyzed since the addition of a radical trap
a 100% atom efficient manner with 0.5 mol% of 2a. To further is not detrimental to the reaction which still proceeds with good
develop this HP transformation beyond proof of principal results yields (94% 3a with 3 mol% cumene, 87% 3a with 3 mol% TEMPO).
and cultivate first row TM-catalyzed applications, we carried out a The presence of a vast excess of cumene has very little effect on the
short investigation into the use of 3a as a ligand in iron-catalyzed reaction (89% 3a with 0.57 mmol cumene) and reaction monitoring
shows very little difference in the reaction profile compared to the
same reaction in the absence of cumene (the initial rate of conver-
Table 1 HP substrate scope
sion to 3a is 0.0626 mmol sꢀ1 for HP in the absence of cumene and
Entry
Alkene
Product
Yielda (spec. yield)b
0.0616 mmol sꢀ1 in the presence of 0.57 mmol cumene, see ESI†).
It is reasonable to invoke a key disproportionation of 2a in
order for the dimer to become active in catalysis20 with homo-
leptic cleavage by HPPh2 forming two equivalents of 2b and
diphenylphosphine oxide. In order to test this hypothesis, 2b
was employed as the pre-catalyst under the standard reaction
conditions, however, to our surprise no reaction is observed as
only starting material remains after 24 h. This was unexpected as
we anticipated that an Fe(II) pre-catalyst would be highly active and
suggests disproportionation of 2a into 2b does not occur. We
hypothesized that proton abstraction from diphenylphosphine
must be necessary for 2b to become catalytically active. Addition
of a base (2 mol% NaOtBu) to the standard catalytic reaction with
1 mol% 2b as the pre-catalyst gives 20% 3a. Increasing the loading
of NaOtBu to 0.57 mmol (1 eq.) gives 66% 3a while 0.57 mmol of
base in the absence of 2b gives only 12% 3a.21 We have extended
our mechanistic investigations to include some kinetic studies of
the synthesis of 3a using 2a (0.5 mol%). Many of these NMR studies
are only possible due to the paramagnetic pre-catalyst 2a being
1
2
3
4
R = H
3a
3b
3c
3d
3e
3f
3g
3h
3i
89 (100)c
79 (96)
89 (97)
65 (82)c
74 (100)d
43 (93)
83 (85)c
58 (85)e
95 (100)c
96 (98)c
89
R = 4-Me
R = 4-OMe
R = 4-Br
5
6
7
8
R = 4-Cl
R = 4-CN
R = 4-CF3
R = 4-Ph
R = 3-Me
R = 3-Br
R = 3,5-OMe
R = 2-OMe
9
10
11
12
3j
3k
3l
62 (87)
13
3m
75 (80)c, f
86 (92) f
14
3n
15
16
R = Me
R = nBu
3o
3p
69 (80)
76 (93)
Conditions: alkene (1.04 mmol, 1.82 eq.), HPPh2 (0.57 mmol, 1 eq.),
2a (1.8 mg, 0.5 mol% 2a (1 mol% Fe-center)), MeCN (0.35 mL), RT, 24 h.
a
b
Isolated yield (%). Spectroscopic yield (%), 1,2-DCE used as a
c
standard. Trace amounts of an unknown impurity co-elute with the
product (see ref. 14). 114 h. 60 1C. 72 h.
d
e
f
Scheme 3 Iron catalyzed Negishi cross-coupling using 3a as the pro-ligand.
12110 | Chem. Commun., 2014, 50, 12109--12111
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9 A chiral iron salen-type complex for hydrophosphorylation is
known: (a) P. Muthupandi and G. Sekar, Org. Biomol. Chem., 2012,
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catalytically active at such low loadings. The turnover frequency for
the formation of 3a over the initial 30 minutes is 80 hꢀ1, slowing to
33 hꢀ1 after 3 hours (at which point the reaction is 44% complete).
The upper turnover number limit is 200 for this reaction (assuming
2a acts as a dimer in the catalytic cycle). A Hammett plot of HP with
2a shows that there is a change in rate limiting step (see ESI†) and
further investigation shows that the order in 2a is 1.6, suggesting a
far more complicated catalytic cycle than originally anticipated
and, at these early stages of our mechanistic studies, we cannot
fully rule out a Michael addition or a 1,2-insertion process.4c
Therefore, a full mechanistic investigation is underway and will
be reported in due course.
In summary, we have developed a simple, air stable iron pre-
catalyst for the hydrophosphination of activated alkenes.
The reaction proceeds with low catalyst loading and at room
temperature. We have also shown that the reaction is unlikely to be
radical mediated. Full mechanistic studies will be reported shortly
and are being used to inform the design of pro-ligands and thus
iron pre-catalysts which will utilize unactivated starting materials
(unactivated alkenes, alkyl phosphines, internal alkenes). In addi-
tion, the obtained phosphine products have shown early promise as
pro-ligands for the Fe-mediated Negishi cross-coupling of benzyl
bromides and diaryl zinc reagents, demonstrating for the first time
the synthetic application of mono-phosphines obtained from HP.
We would like to thank Dr M. F. Mahon for assistance with
X-ray crystallography (characterisation of 2a) and the EPSRC NMSF
at the University of Swansea for mass spectrometry analyses. We
would like to thank the University of Bath for a Prize Fellowship
(RLW) and a DTA studentship (KJG).
16 H.-H. Chou and R. T. Raines, J. Am. Chem. Soc., 2013, 135, 14936–14939.
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´
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added to a solution of ZnCl2 (136 mg, 1 mmol) in THF (0.5 mL) and
stirred under N2 for 30 min. Toluene (4 mL) was added, followed by
the appropriate benzyl bromide (1 mmol). The mixture was trans-
ferred by cannula to a stirred solution of FeCl2 (6 mg, 5 mol%) and
3a (87 mg, 0.3 mmol) in toluene (1 mL), washing the ZnPh2 solution
through with toluene (2 mL). The reaction was stirred at 45 1C for
14 h, quenched with H2O, extracted into EtOAc and analyzed by
1H NMR spectroscopy using 1,3,5-trimethoxybenzene as a standard.
The reaction has not been fully optimized: reduced yields are due to
homocoupling and/or unreacted benzylic starting material.
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tion, therefore 6 eq. mono-phosphine (0.3 mmol) was used in this report.
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14704–14705. Selected examples with Cu:; (c) N. A. Isley,
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´
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8 L. Routaboul, F. Toulgoat, J. Gatignol, J.-F. Lohier, B. Norah,
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(a) E. Shirakawa, K.-I. Itoh, T. Higashino and T. Hayashi, J. Am. Chem.
Soc., 2010, 132, 15537–15539. Addition of 1 eq. cumene to the catalytic
reaction of 2b (1 mol%) with styrene (1.82 eq.), HPPh2 (0.57 mmol, 1 eq.)
and NaOtBu (1 eq.) give a spectroscopic yield of 87% 3a. Use of NEt3
(20 mol%) in the standard transformation with 2b gives 32% 3a.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 12109--12111 | 12111