Iron-catalysed alkene hydrogenation and reductive cross-coupling using a bench-stable iron(II) pre-catalyst

Article abstract of DOI:10.1039/c3ra44519d

Operationally simple, iron-catalysed hydrogenation and reductive cross-coupling protocols have been developed using a bench-stable iron(ii) pre-catalyst. The hydrogenation of 18 alkenes (50-99%) and reductive cross-coupling of vinyl halides with aryl- and alkyl Grignard reagents (8 examples, 18-99%) is reported using 3 mol% pre-catalyst and hydrogen as stoichiometric reductant (1-50 bar).

Full text of DOI:10.1039/c3ra44519d

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Iron-catalysed alkene hydrogenation and reductive
cross-coupling using a bench-stable iron(II) pre-
catalyst†‡
Cite this: RSC Adv., 2013, 3, 25698
a
b
b
b
Received 20th August 2013
Accepted 23rd October 2013
´
¨
Dominik J. Frank, Lea Guiet, Alexander Kaslin, Elliot Murphy
a
*
and Stephen P. Thomas
DOI: 10.1039/c3ra44519d
www.rsc.org/advances
Operationally simple, iron-catalysed hydrogenation and reductive reactivity of the proposed catalytically active low-valent iron
cross-coupling protocols have been developed using a bench-stable species5 for the hydrogenation of alkenes whilst maintaining
iron(II) pre-catalyst. The hydrogenation of 18 alkenes (50–99%) and the operational simplicity of the cross-coupling reactions. The
reductive cross-coupling of vinyl halides with aryl- and alkyl Grignard active catalyst would be generated by the reduction of a bench-
reagents (8 examples, 18–99%) is reported using 3 mol% pre-catalyst stable Fe(II/III) salt with an organometallic coupling reagent
and hydrogen as stoichiometric reductant (1–50 bar).
(4 equivalents with respect to iron pre-catalyst).5d Thus, a sub-
stoichiometric amount of a Grignard reagent could be used to
activate an Fe(II) pre-catalyst in situ, giving a low-valent iron
species without the need to handle a highly air- and moisture
sensitive iron complex (Fig. 1, A). Further, if the active species
from an iron catalysed cross-coupling was to be used, could we
combine the hydrogenation with an iron-catalysed cross-
coupling to give a reductive cross-coupling6 with hydrogen
acting as the stoichiometric reductant (Fig. 1, B).
Using 1-phenyl-1-butene as a model substrate, a series of
multidentate nitrogen ligands were screened in conjunction
with iron(II) chloride for hydrogenation activity (Table 1). It was
found that increasing the number of coordination sites on the
ligand gave higher conversion and that 50 bar hydrogen pres-
sure was needed. Presumably the tetradentate ligand (ꢀ)-3
extends catalyst lifetime and the elevated hydrogen pressure
ensures efficient turnover. Optimised hydrogenation conditions
required 3 mol% FeCl2, 3 mol% ligand (ꢀ)-3 and 15 mol%
iPrMgCl (as pre-catalyst activator) at 50 bar hydrogen pressure
(Table 1, entry 6). Use of high-purity FeCl2 showed equal activity
and in the absence of iron no hydrogenation was observed.7
ICP-MS analysis of the reaction mixture showed the amount of
other transition metals to be well below catalytically active
Olen hydrogenation is one of the most used reactions in both
academic and industrial settings having broad applications in
biological, pharmaceutical and ne chemical products.1 To
date, olen hydrogenation has been dominated by the use of
precious and toxic transition metal catalysts such as the plat-
inum group metals. The replacement of these metals with more
economical, abundant and sustainable elements is therefore at
the forefront of progress and future applications of hydroge-
nation. Although great progress has been made using the
traditional transition metal catalysts with respect to functional
group tolerance, substrate scope and enantioselective variants,
the use of iron catalysts has lagged behind. Recently, low-valent
iron species have been shown to catalyse the hydrogenation of
mono, disubstituted and trisubstituted alkenes with excellent
activity for both functionalised and unfunctionalised alkenes.2,3
These iron complexes however suffer from high sensitivity to
both oxygen and water and/or require prior synthesis, reducing
the appeal of these systems from a practicality point of view
compared to heterogeneous methods (e.g. Pd/C–H2).
Taking inspiration from iron-catalysed cross-coupling reac-
tions,4 where a highly active low-valent iron species is generated
in situ from a bench-stable pre-catalysts, we sought to exploit the
aSchool of Chemistry, Joseph Black Building, University of Edinburgh, West Mains
Road, Edinburgh, Scotland EH9 3JJ, UK. E-mail: stephen.thomas@ed.ac.uk; Tel: +44
(0)131 650 4726
bSchool of Chemistry, University of Bristol, Cantock's Close, Bristol, England BS8 1TS,
UK
† Celebrating 300 years of Chemistry at Edinburgh.
‡ Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra44519d
Fig. 1 Iron-catalysed, hydrogenation and reductive cross-coupling.
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Table 1 Iron-catalysed hydrogenation of 1-phenyl-1-butenea
Table 2 Scope of the iron-catalysed hydrogenationa
Entry
1
Substrate
Product
Yieldb [%]
99c, 99d
2
3
91
92
Entry
L
H2 [bar]
Time [h]
Conv.b [%]
1
2
3
4
5
6
7
8
—
—
1
1
2
2
3
3
1
50
1
50
1
50
1
50
6
18
6
18
6
18
6
3
0
0
0
>5
0
33
12
99
4
92
5
6
7
99
99
a
Conditions: 3 mol% FeCl2, 3.2 mol% L, THF (0.2 M), 15 mol% iPrMgCl
b
(2 M in THF), ꢁ20 ꢂC then 1–50 bar H2, ꢁ20 ꢂC / rt, 1 h. As
90
determined by GC-MS.
75
96
8
9
levels.7 Although we can not rule out iron nanoparticles (FeNPs)
as the active catalyst, the failure of the hydrogenation in the
absence of ligand and the lack of a maturation period3 during
catalyst activation would suggest against a FeNP-catalysed
10
96c, 78e
99f, 90g
process. Presumably the multidentate ligand ensures a discrete, 11
homogeneous, low-valent iron species is generated during
activation and acts as the active catalyst.2
12
50
83
We next investigated the scope and limitations of our
system. Styrene was quantitatively reduced, even at low
hydrogen pressure and, interestingly, in the absence of ligand
(ꢀ)-3 (Table 2, entry 1). However this did not prove to be general
13
and all other alkenes tested required elevated H2 pressure and
14
X ¼ F
87
74
—
93
ligand (ꢀ)-3 for effective hydrogenation. Styrene derivatives
bearing ortho-, meta- or para-alkyl groups were all reduced in
excellent yield, including 2,4,6-trimethylstyrene (Table 2,
entries 2–5). Alkyl substituted alkenes were readily hydroge-
nated (entries 6 and 7). Internal alkenes trans-methylstyrene
and cis- and trans-stilbene were hydrogenated in 75% and
near-quantitative yield, respectively (entries 8–10). The 1,1-
disubstituted alkene, a-methylstyrene, was hydrogenated in
quantitative yield, even at only 10 bar H2 pressure (entry 11).
Electron-rich and electron-decient styrene derivatives were
hydrogenated in excellent yields (entries 12–15) with the
exception of 4-cyanostyrene (entry 16). Presumably, the nitrile
group irreversibly coordinates the iron catalysts. In the case of
2-chloro- and 4-chlorostyrene, hydrogenation proceeded
without proto-dehalogenation8 or vinyl directed cross-coupling9
(entries 12 and 13).
15
16
17
X ¼ OMe
X ¼ CN
18
19
99
66, 99h
20
—
a
Conditions: 3 mol% FeCl2, 3.2 mol% (ꢀ)-3, THF (0.2 M), 15 mol%
iPrMgCl (2 M in THF), 50 bar H2, ꢁ20 ꢂC / rt, 16 h. As determined
b
by GC-MS or 1H NMR using an internal standard. In the absence of
c
d
e
O-Benzyl protected styrene derivative and silyl protected
alcohol were chemoselectively hydrogenated at the alkene
without loss of the protecting groups (entries 17 and 18) and an
ligand (ꢀ)-3, 1 h reaction time. 1 bar H2, 3 h reaction time. In the
f
g
absence of ligand (ꢀ)-3. 5 h reaction time. 10 bar H2, 3 h reaction
time. h 6 mol% catalyst, 30 mol% iPrMgCl.
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aryl ester could also be reduced in 99% yield with no addition of signicant amounts of recovered starting material, not inter-
the Grignard to the carbonyl group, albeit with 6 mol% FeCl2 mediate alkene as observed when using iPrMgCl.
and (ꢀ)-3 (entry 19). Unfortunately, and in common with
An equal yield of reductive cross-coupling was obtained for
previous iron-catalysed hydrogenations,2,3 our system was b-chlorostyrene (entry 8), with respect to that using b-bromos-
inactive for the hydrogenation of trisubstituted alkenes tyrene. However, use of b-iodostyrene or an enol triate as the
(entry 20).2h
electrophilic coupling partner, gave only the intermediate
Having developed an iron-catalysed alkene hydrogenation alkene, from cross-coupling only (entries 9 and 10). An unsub-
we were keen to expand the utility of the reaction by carrying out stituted vinyl halide was also tested and found to undergo
tandem, one-pot, cross-coupling and reduction reactions; a successful undergo reductive cross-coupling (entry 11).
reductive cross-coupling.6 This would be achieved by using the
In summary, we have developed a simple iron-catalysed
developed iron(II) pre-catalysts as a single catalyst for both the hydrogenation of alkenes and reductive cross-coupling of vinyl
cross-coupling of a vinyl halide and Grignard reagent and a halides and Grignard reagents using a bench-stable iron(II)
subsequent hydrogenation. The overall transformation formally pre-catalyst. By generating a low-valent iron catalyst in situ,
gives the product of a sp3–sp3 cross-coupling reaction.
mono-, 1,1- and 1,2-disubstituted aryl- and alkyl alkenes were
By directly applying our developed hydrogenation condi- hydrogenated in good to excellent isolated yield. The iron(II)
tions, but using a stoichiometric amount of Grignard reagent pre-catalyst was further applied to the reductive cross-coupling
(as activator and coupling partner), b-bromostyrene and ethyl- of vinyl halides and Grignard reagents, under hydrogen, to give
magnesium chloride were reductively cross-coupled to give the products of formal sp3–sp3 cross-coupling reactions.
butylbenzene quantitatively (99% isolated yield; Table 3, Successful reductive cross-coupling was observed for vinyl
entry 1). It should be noted that in the absence of ligand (ꢀ)-3 bromides with aryl- and alkyl Grignard reagents and a vinyl
only cross-coupling was observed. High reductive cross- chloride.
coupling yields were achieved using iso-propylmagnesium
We thank Dr Corey Archer and Prof. Tim Elliott (UoB) for
chloride and phenethylmagnesium chloride (entries 2 and 3). ICP-MS analyses and EPSRC for funding (EP/I036281/1).
The only observed by-product from these reactions was the
intermediate alkene, which had not been hydrogenated within
the reaction time. Surprisingly, when using Grignard reagents
Notes and references
without, or lacking readily available, b-hydrogens (PhMgCl, 1 (a) A. Corma, S. Iborra and A. Velty, Chem. Rev., 2007, 107,
MeMgCl and AllylMgCl), reductive cross-coupling was shown to
proceed in very good yield (entries 4, 6 and 7). Presumably an
iron super-ate complex6 is now catalysing both cross-coupling
and hydrogenation. In the case of tert-butylmagnesium chlo-
ride, cross-coupling now became yield limiting (entry 5) with
2411; (b) Handbook of Homogeneous Hydrogenation, ed. J. G.
de Vries and C. J. Elsevier, Wiley-VCH, Weinheim, Germany,
2007; (c) N. B. Johnson, I. C. Lennon, P. H. Moran and
J. A. Ramsden, Acc. Chem. Res., 2007, 40, 1291; (d) F. Naud,
F. Spindler, C. J. Rueggeberg, A. T. Schmidt and
H. U. Blaser, Org. Process Res. Dev., 2007, 11, 519.
2 (a) C. Bianchini, E. Farnetti, M. Graziano, M. Peruzzini and
A. Polo, Organometallics, 1993, 12, 3753; (b) E. J. Daida and
J. C. Peters, Inorg. Chem., 2004, 43, 7474; (c) S. C. Bart,
E. Lobkovsky and P. J. Chirik, J. Am. Chem. Soc., 2004, 126,
13794; (d) S. C. Bart, E. J. Hawrelak, E. Lobkovsky and
P. J. Chirik, Organometallics, 2005, 24, 5518; (e)
R. J. Trovitch, E. Lobkovsky and P. J. Chirik, Inorg. Chem.,
2006, 45, 7252; (f) S. C. Bart, K. Chlopek, E. Bill,
M. W. Bouwkamp, E. Lobkovsky, F. Neese, K. Wieghardt
and P. J. Chirik, J. Am. Chem. Soc., 2006, 128, 13901; (g)
R. J. Trovitch, E. Lobkovsky, E. Bill and P. J. Chirik,
Organometallics, 2008, 27, 1470; (h) R. Pony Yu,
J. M. Darmon, J. M. Hoyt, G. W. Margulieux, Z. R. Turner
and P. J. Chirik, ACS Catal., 2012, 2, 1760; (i) A. Welther,
M. Bauer, M. Mayer and A. Jacobi von Wangelin,
ChemCatChem, 2012, 4, 1088.
Table 3 Scope of the iron-catalysed reductive cross-couplinga
Entry
R1
X
R2
Yieldb [%]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
Br
Br
Br
Br
Br
Br
Br
Cl
I
Et
99
84
iPr
Ph(CH2)2
Ph
tBu
Allyl
Me
Et
Et
Et
Tol
79c
78d
18e
43
40
94f
g
3 (a) P.-H. Phua, L. LeFort, J. A. F. Boogers, M. Tristany and
J. G. de Vries, Chem. Commun., 2009, 3747; (b)
9
—
c,g
10
OTf
Br
—
11h
68c
´
C. Rangheard, C. de J. Fernandez, P.-H. Phua, J. Hoorn,
a
Conditions: 3.5 mol% [Cl2Fe(ꢀ)-3], THF (0.2 M), 150 mol% R2MgCl (2 M
L. Lefort and J. G. de Vries, Dalton Trans., 2010, 39, 8464.
4 For reviews see: (a) E. Nakamura and N. Yoshikai, J. Org.
Chem., 2010, 75, 6061; (b) W. M. Czaplik, M. Mayer,
J. Cvengros and A. Jacobi von Wangelin, ChemSusChem,
2009, 2, 396; (c) A. Leitner, in Iron Catalysis in Organic
in THF), 50 bar H2, ꢁ20 ꢂC / rt, 18 h. b Determined by 1H NMR, GC-MS
and 13C NMR of isolated product. Conversion, determined by GC-MS
c
and 1H NMR of the crude reaction mixture. 15% biphenyl isolated.
d
e
g
f
50% 1,4-diphenyl-butane isolated. 6% 1,4-diphenyl-butane isolated.
Cross-coupled only observed. h TolMgBr (1 M in THF) used.
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Chemistry: Reactions and Applications, ed. B. Pleitker, Wiley-
VCH, Weinheim, Germany, 2008, pp. 147–176; (d)
M. Nakamura, K. Matsuo, S. Ito and E. Nakamura, J. Am.
Chem. Soc., 2004, 126, 3686.
¨
A. Rudolph and M. Lautens, Angew. Chem., Int. Ed., 2009, 5 (a) J. Kleimark, P.-F. Larsson, P. Emamy, A. Hedstrom and
¨
48, 2656; (e) B. M. Sherry and A. Furstner, Acc. Chem. Res.,
P.-O. Norrby, Adv. Synth. Catal., 2012, 354, 448 and
previous papers cited therein; (b) J. Yang and T. D. Tilley,
¨
2008, 41, 1500; (f) A. Furstner and R. Martin, Chem. Lett.,
¨
2005, 34, 624. For selected recent examples see: (g)
M. D. Greenhalgh and S. P. Thomas, J. Am. Chem. Soc.,
2012, 134, 11900; (h) A. K. Steib, T. Thaler, K. Komeyama,
P. Mayer and P. Knochel, Angew. Chem., Int. Ed., 2011, 50,
3303; (i) W. M. Czaplik, M. Mayer and A. Jacobi von
Angew. Chem., Int. Ed., 2010, 49, 10186; (c) A. Furstner,
R. Martin, H. Krause, G. Seidel, R. Goddarda and
C. W. Lehmann, J. Am. Chem. Soc., 2008, 130, 8773; (d)
B. Bogdanovic and M. Schwickardi, Angew. Chem., Int. Ed.,
´
2000, 39, 4610.
Wangelin, ChemCatChem, 2011, 3, 135; (j) M. Mayer, 6 B. A. F. Le Bailly, M. D. Greenhalgh and S. P. Thomas, Chem.
W. M. Czaplik and A. Jacobi von Wangelin, Adv. Commun., 2012, 48, 1580.
Synth.Catal., 2010, 352, 2147; (k) R. B. Bedford, M. Huwe 7 See ESI‡ for details.
and M. C. Wilkinson, Chem. Commun., 2009, 600; (l) 8 W. M. Czaplik, S. Grupe, M. Mayer and A. Jacobi von
G. Cahiez, V. Habiak, C. Duplais and A. Moyeux, Angew.
Wangelin, Chem. Commun., 2010, 46, 6350.
¨
Chem., Int. Ed., 2007, 46, 4364; (m) R. Martin and 9 S. Gulak and A. Jacobi von Wangelin, Angew. Chem., Int. Ed.,
¨
A. Furstner, Angew. Chem., Int. Ed., 2004, 43, 3955; (n)
2012, 51, 1357.
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