Iron as a Powerful Catalysts for Transition MetalCatalyzed Reactions
David J. Michaelis
1101 University Ave. Madison, WI 53605
vidmichaelis@chem.wisc.edu
Received Date (will be automatically inserted after manuscript is accepted)
ABSTRACT
Iron has received a significant amount of attention in the recent literature as a powerful catalyst for transition metalcatalyzed reactions. Due to its low cost, ready abundance, and low toxicity, iron is an ideal metal catalyst for large
scale synthesis of fine chemicals. The development of iron-catalyzed processes, however, is still in its infancy. This
review will provide a direct comparison between state-of-the-art transition metal-catalyzed reactions and recent
efforts to employ iron as a catalyst for the equivalent transformations. Reactions of high synthetic impact including
Kumada couplings, hydrogenative reductions, and dihydroxylations will be covered in this review.
Transition metal-catalyzed reactions are among the
most powerful tools in organic synthesis. Extensive
research effort has been invested in the development of
palladium-, ruthenium-, rhodium-, iridium-, and even
nickel-catalyzed reactions. Due, however, to the high
cost and toxic nature of many of these metal catalysts,
there has been a recent surge in reports of organic
transformations catalyzed by cheaper and more
environmentally friendly metals such as copper1 and
iron.2 In particular, iron-catalyzed reactions have several
practical advantages over the analogous palladium- or
nickel-mediated reactions. The low cost and ample
supply of iron salts coupled with their environmentally
benign nature and lack of toxicity make them ideal for
industrial scale synthesis of fine chemicals. Iron has
recently received a significant amount of attention in the
literature as a catalyst for allylic substitution reactions3,
1
For recent examples see: (a) Do, H.-Q.; Daugulis, O. J. Am. Chem.
Soc. 2007, 127, 12404–12405. (b) Ma, D.; Liu, F. Chem. Commun.
2004, 1934–1935. (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400–5449.
2
For a recent review see: Bolm, C.; Legros, J.; Le Paih, J.; Zani, L.
Chem. Rev. 2004, 104, 6217–6254. Enthaler, S.; Junge, K.; Beller, M.
Angew. Chem. Int. Ed. 2008, 47, 3317–3321.
3
(a) Plietker, B. Angew. Chem. Int. Ed. 2006, 45, 6053–6056. (b)
Åkermark, B.; Sjögren, M. P. T. Adv. Synth. Catal. 2007, 349, 2641–
2646
dihydroxylations of olefins,4 epoxidation and C–H
oxygenation reactions,5 hydrogenation of ketones, and
cross-couplings of organic halides with organometallic
reagents.6
While iron is often considered a latecomer in the
development of transition metal catalyzed reactions, the
use of iron as a transition metal catalyst, in fact, preceeds
the use of palladium and other more common metals as
catalysts. As early as 1941, iron was found to be an
effective catatlyst in the homocoupling of aryl Grignard
reagents7, and in the early 1950s iron was used as a
catalyst for cross-coupling Grignard reagents with acid
chlorides (Scheme 1)8. In the ensuing years, iron was set
aside due to the control and predicability that came with
such metals as palladium or ruthenium. Not until recently
4
See: Oldenburg, P. D.; Que Jr., L. Catalysis Today 2006, 117, 15–
21, and references therein.
5
For epoxidation see: Lane, B. S.; Burgess, K. Chem. Rev. 2003, 103,
2457–2474. For C–H oxidation reactions see: Chen, M. S.; White, M. C.
Science, 2007, 318, 783–787, and references therein.
6
(a) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651–2710.
(b) Frisch, A. C.; Beller, M. Angew. Chem. Int. Ed. 2005, 44, 674–688.
(c) “Metal-catalyzed cross-coupling reactions, Vol. 1-2: second edition,”
ed. By A. de Meijere and F. Diederich, Wiley-VCH, Weinheim (2004).
7
Kharasch, M.; Fields, E. J. Am. Chem. Soc. 1941, 63, 2316–2320.
8
Percival, W. C.; Wagner, R. B.; Cook, N. C. J. Am. Chem. Soc.
1953, 75, 3732–3734.
Scheme 1. Iron-catalyzed synthesis of ketones.
has iron begun to receive much attention again, due in the
most part to its advantages of low cost and low toxicity.
Several recent reviews have described the advances in
iron catalysis and its potential as a powerful transition
metal catalyst.2 However, no direct comparisons between
the iron-catalyzed and the traditional transition metalcatalyzed reactions have been made. The purpose of this
review is to provide such comparisons that will
demonstrate the potential of iron to supplant the use of
more expensive and potentially hazardous metal catalysts.
The development of iron-catalyzed Kumada crosscoupling reactions, hydrogenative reductions, and
dihydroxylation reactions have recently shown significant
potential as useful transformations and thus will be the
focus of further discussion.
Kumada cross-coupling reaction. The Kumada
coupling reaction was first reported in 1972 by Kumada
and coworkers and involved a nickel-catalyzed coupling
between an aryl Grignard reagent and a vinyl chloride.9
Later, palladium was also shown to affect the same
process with both aryl and vinyl halides.10 The state of
the art in Kumada cross-couplings today includes low
temperature
cross-couplings
of
functionalized
organomagnesium reagents and cross-couplings with
unactivated alkyl halides. Buchwald and coworkers
recently demonstrated that an aryl iodide can be crosscoupled with an organomagnesium reagent in the
presence of Cyano groups, esters, and heterocycles such
as furans and thiophenes.
This transformation is
performed in high yield utilizing only 2 mol% Pd(DBA)2
in the presence of a
bidentate phosphine ligand (Scheme 2).11 In addition to
aryl-aryl bond formation, cross-couplings that generate
new aryl-alkyl C–C bonds12 as well as alkyl-alkyl C–C
bonds13 are also possible. For example, Kambe and
coworkers recently reported the cross-coupling of nonactivated alkyl halides and tosylates with alkyl
magnesium bromide reagents (Scheme 2).
Intense development of iron-catalyzed Kumada
couplings has recently been pursued.14 Utilizing readily
available iron(III) salts such as Fe(acac)3, cross-couplings
of aryl or alkyl Grignard reagents with alkyl or aryl
halides or sulfonates are easily accomplished. Fürstner
and coworkers have suggested that in situ reduction of
iron(II) or iron(III) salts by the corresponding Grignard
reagent generates highly active Fe(-II) catalysts, which
perform the cross-coupling reaction even at extremely
low temperatures.15,16 Fürstner has shown that these Fe(II) catalysts can be used to cross-coupling aryl chlorides,
triflates, and even tosylates in high yield (Scheme 3).17
Scheme 3. Kumada cross-coupling reactions with iron.
Scheme 2. Kumada cross-couplings with Pd and Ni.
A significant advantage of this iron-catalyzed process
is that it precludes the need for highly specialized and
expensive ligands. Thus, under ligand-free conditions,
alkyl magnesium bromide reagents react with aryl or
alkyl halides at extremely low temperatures, tolerating
such functional groups as esters, ketones and cyanides.
Only when cross-coupling secondary alkyl halides with
alkyl or aryl Grignard reagents has the use of stabilizing
ligands proved necessary to prevent alternative reaction
pathways. In these cases, coordinating phosphine18 and
amine-bisphenolate19 ligands have allowed for highly
efficient reactions (Scheme 4).
The above results demonstrate that iron rivals the
traditional palladium- and nickel-catalyzed Kumada
coupling reactions in terms of reaction efficiency. Ligand
9
Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94,
4374–4376.
10
Yamamura, M.; Moritani, I.; Murahashi, S.-I. J. Organometallic
Chem. 1975, 91, C39–C42.
11
Martin, R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3844–
3845.
12
Frisch, A. C.; Shaikh, N.; Zapf, A.; Beller, M. Angew. Chem. Int. Ed.
2002, 41, 4056–4059.
13
Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J.
Am. Chem. Soc. 2002, 124, 4222–4223.
14
For reviews see: (a) Fürstner, A.; Martin, R. Chem. Lett. 2005, 34,
624–629. (b) Fürstner, A.; Leitner, A.; Ménendez, M.’ Krause, H. J. Am.
Chem. Soc. 2002, 124, 13856–13863. “Iron-catalyzed cross-coupling
reactions.”
15
Martin, R.; Fürstner, A. Angew. Chem. Int Ed. 2004, 43, 3955–
3957.
16
Under certain conditions, Fe(0) and Fe(II) catalysts have also been
proposed. See: (a) Fürstner, A.; Krause, H.; Lehmann, C. W. Angew.
Chem., Int. Ed. 2006, 45, 440–444. (b) Cahiez, G.; Habiak, V.; Duplais,
C.; Moyeux, A.; Angew. Chem. Int. Ed. 2007, 46, 4364–4366
17
Fürstner, A.; Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609-612.
18
Dongol, K. G.; Koh, H.; Sau, M.; Chai, C. L. L. Adv. Synth. Catal.
2007, 349, 1015–1018
19
Chowdhury, R. R.; Crane, A. K.; Fowler, C.; Kwong, P.; Kozak, C.
M. Chem. Commun. 2008, 94–96.
Scheme 4. Ligands for iron-catalyzed Kumada couplings.
Scheme 5. Iron-catalyzed hydrogenations.
O
H2, 3 atm
2, 2 mol%
Toluene, 36 h
free reaction conditions and moderate functional group
tolerance are often possible with iron-catalyzed Kumada
couplings. These facts, in addition to the low cost and
low environmental impact of iron salts should make iron
the catalyst of choice for a wide range of cross-coupling
reactions.
Hydrogenations. The asymmetric hydrogenation of
alkenes and polar bonds such as ketones and imines is a
powerful strategy for generating chiral molecules.
Indeed, an immense amount of research has been
performed to generate efficient and selective
hydrogenation reactions with ruthenium and iridium for
use both in research laboratories and on the industrial
scale.20 Asymmetric hydrogenation has been used as the
key step in the synthesis of pharmaceutical compounds21
on scale and of herbicides on multi-ton scales.22
Although the field of transition metal-catalyzed
asymmetric hydrogenations is quite mature, iron has
shown a growing potential as a highly efficient and cost
effective alternative to other homogeneous catalysts. An
important variable in catalyst choice for hydrogenations
is turnover frequency (TOF) which gives an indication of
rate and catalyst loading needed. Chirik and coworkers
have shown that iron complex 1 can perform
hydrogenations of simple alkenes with turnover
frequencies superior to many ruthenium- or iridiumcatalyzed processes (Scheme 5).23 The system lacks
generality, however, giving significantly lower turnover
numbers for reductions of aromatic alkenes and enones.
Casey and coworkers described the first well-defined
iron catalyst for the hydrogenation of ketones using
catalyst 2.24 In their system, ketones can be reduced
selectively in the presence of sensitive functional groups
groups such as halides, alkenes, and alkynes. This
20
See Acc. Chem. Res. 2007, 40(12) for a special issue focused on
hydrogenation and transfer hydrogenation reactions.
21
Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008–2022.
22
Asymmetric Catalysis in Industrial Scale: Challenges, Approaches
and Solutions; Blaser, H. U., Schmidt, E., Eds.; Wiley: Weinheim,
Germany, 2003.
23
Bart, S. C.; Lobkovsky, E.; Chirik, P. J. J. Am. Chem. Soc. 2004,
126, 13794–13807.
24
Casey, C. P.; Guan, H. J. Am. Chem. Soc. 2007, 129, 5816–5817.
OH
87%
TMS
O
2=
H
TMS
Fe
OC
H
OC
selectivity stems from the bifunctional nature of the
catalyst as both a hydride and a proton donor, allowing
for the selective reduction of polar bonds.
Two
drawbacks to this reaction, however, include long
reaction times and the fact that only ketones react
efficiently with this catalytic system. Nevertheless, these
early reports demonstrate the ability of iron catalysts to
affect these important and widely used transformations.
Although asymmetric hydrogenations with iron have
yet to appear in the literature, recent examples of
asymmetric transfer hydrogenations and hydrosilations of
ketones have established the ability of iron to affect such
asymmetric reactions.25 The most recent results of Beller
and coworkers demonstrate the ability of iron-phosphine
complexes to perform highly selective reduction
reactions. Utilizing sterically hindered aryl ketones, they
were able to obtain excellent yields with almost absolute
selectivity (Scheme 6). While this system is obviously
limited by the constraints of the substrate, it provides a
foundation for the development of highly selective ironcatalyzed reductions.
Scheme 6. Asymmetric hydrogenation with iron.
In the field of asymmetric hydrogenation, iron has just
begun to establish a presence. These early examples of
iron-catalyzed
hydrogenations
and
transfer
hydrogenations bespeak the potential of iron to replace
more expensive and hazardous metal catalysts as an
efficient, cost effective and selective alternative.
However, significant improvements in both reactivity and
25
(a) Sui-Seng, C.; Freutel, F.; Lough, A. J.; Morris, R. H. Angew.
Chem. Int. Ed. 2008, 47, 940–943. (b) Nishiyama, H.; Furuta, A.; Chem.
Commun. 2007, 7, 760–764. (c) Shaikh, N. Enthaler, S.; Junge, K.;
Beller, M. Angew. Chem. Int. Ed. 2008, 47, 2497–2501.
selectivity are needed if iron is to become a viable
alternative to existing hydrogenation protocols.
Dihydroxylation of olefins. The osmium-catalyzed
dihydroxylation of olefins is an indispensible tool in
organic synthesis for the generation of chiral diols.26
With the advent of the AD-mix-α and β formulations, this
process has become operationally simple and widely used
for small-scale asymmetric dihydroxylations.
The
Sharpless asymmetric dihydroxylation is particularly
useful due to the wide range of olefins that can be
dihydroxylated with excellent enantioselectivity. These
olefins include simple alkenes, skipped polyenes,
styrenes, and allylic alcohols just to name a few.26
Osmium-catalyzed dihydroxylations are also amenable to
large scale synthesis, as seen in a recent report by Sutin
and coworkers where kilogram quantities of highly
enantioenriched product was obtained (Scheme 7).27
The major drawbacks of the Sharpless asymmetric
dihydroxylation are the high cost and extreme toxicity of
osmium salts.
While catalyst loadings for this
transformation are often below 1 mol%, large scale
syntheses utilizing tens of grams of osmium salts are still
problematic due to the toxicity of the waste generated.
To address this issue, researchers have looked to other
metal sources to affect this transformation, most notably
to palladium.28 In a recent example, Dong and coworkers
found that efficient diacetoxylations of olefins could be
performed with as little as 2 mol% Pd(dppp) (Scheme
7).29 While this transformation provides a significant
alternative to the osmium-catalyzed process, it still
employs an expensive transition metal catalyst.
enzymes could perform efficient dihydroxylations with
hydrogen peroxide as the terminal oxidant.30 While the
corresponding epoxidation of the olefin was a major
competing side reaction, Que has shown that the
dihydroxylation can be favored by varying the structure
of the catalyst (Scheme 8).31 It is important to note that
these iron-catalyzed transformations proceed efficiently
at very low catalyst loadings, and that costly organic
oxidants such as NMO can be replaced with hydrogen
peroxide. When employing a chiral polyamine catalyst,
high levels of enantioselectivity have also been obtained
(Scheme 8).32 While high ee values are obtained with a
variety of trans-disubstituted olefins, the generality of the
reaction is limited as cis alkenes and alkenes bearing
electron withdrawing groups react with only modest
selectivity (up to 76% ee). These early results, however
have shown that iron catalysts can provide an efficient
and highly enantioselective alternative to the existing
osmium-catalyzed methodologies.
Scheme 8. Iron-catalyzed dihydroxylations.
Scheme 7. Dihydroxylation reactions.
[Pd(dppp)(H2O)2](OTf)2 2 mol %
PhI(OAc)2 1.1 equiv
Ph
OAc
Ph
OBn
H2O 3 equiv
AcOH, 50 °C
OBn
OAc
Iron has recently been reported to be an efficient
catalyst for the dihydroxylation of olefins. Que and
coworkers reported that biomimetic iron complexes
inspired by the Rieske dioxygenase nonheme iron
26
For recent reviews see: (a) Christie, S. D. R.; Warrington, A. D.
Synthesis, 2008, 9, 1325–1341. (b) Zaitsev, A. B.; Adolfsson, H.
Synthesis 2006, 7, 1725–1756.
27
Ahrgren, L.; Sutin, L. Org. Process Res. Dev. 1997, 1, 425-427.
28
For early examples see: (a) Gligorich, K. M.; Schultz, M. J.;
Sigman, M. S. J. Am. Chem. Soc. 2006, 128, 2794–2795. (b) Zhang, Y.;
Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 3076–3077.
29
Li, Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008, 130,
2962–2963.
Conclusion. While the field of transition metalcatalyzed reactions continues to produce new and
important transformations, a growing body of research is
focusing on replacing expensive transition metal catalysts
with cheaper, more environmentally friendly and
sustainable metals such as iron.
The wealth of
knowledge concerning reaction pathways that is available
for transition metal-catalyzed reactions will continue to
foster growth of well defined catalytic systems with iron.
This review focuses on only three of the many important
transition metal-catalyzed reactions and the ability of iron
to affect these processes. The precedents described here
suggests that iron will continue to appear as a viable
alternative transition metal catalyst that is cost effective,
nontoxic, and environmentally benign.
30
Costas, M.; Tipton, A. K.; Chen, K.; Jo, D.-H.; Que, Jr., L. J. Am.
Chem. Soc. 2001, 123, 6722–6723.
31
Oldenburg, P. D.; Shteinman, A. A.; Que, Jr., L. J. Am. Chem. Soc.
2005, 127, 15672–15673.
32
Suzuki, K.; Oldenburg, P. D.; Que, Jr., A. Angew. Chem. Int. Ed.
2008, 47, 1887–1889.