Document type: Review/Account

Account/Review for Frontiers of Molecular Science

Iron Catalyzed C­C-Bond Formation: From Canonical Cross Coupling

to a Quest for New Reactivity#

Alois Fürstner

Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany

E-mail: fuerstner@kofo.mpg.de

Received: October 9, 2020; Accepted: November 9, 2020; Web Released: November 17, 2020

Alois Fürstner
Alois Fürstner obtained his doctoral degree in 1987 from the Technical University of Graz, Austria. After a
postdoctoral stint in Geneva, Switzerland, and a Habilitation in Graz, he joined the Max-Planck-Institut für
Kohlenforschung, Mülheim, Germany, in 1993. In 1998, he was promoted to the rank of Director. His
research is focused on organometallic catalysis, ranging from fundamental mechanistic studies to appli-
cations in target-oriented synthesis. He received numerous awards, including the Thieme/IUPAC Prize
(2000), the ACS Arthur C. Cope Scholar Award (2002), the Mukaiyama Award (2005), the Otto-Bayer-Prize
(2006), the Janssen Pharmaceutica Prize (2008), the Prelog Medal (2011), the Karl-Ziegler-Prize (2013), the
Kitasato Medal (2013), the ACS H. C. Brown Award (2016), and the Prix Mondial Nessim Habif (2019).

Abstract questions. As a consequence, research into base metal catalysis

This Account summarizes our work in the area of organoiron
chemistry during the last two decades, with special emphasis
on iron catalyzed C-C-bond formation. Specifically, it is shown
that iron catalysts can emulate reactivity more befitting noble
metals in that they allow various cross coupling, cycloaddition
and cycloisomerization reactions to be carried out with sur-
prising ease. At the same time, this base metal opens oppor-
tunities for the discovery of genuinely new transformations.
Keywords: Iron catalysis j Cross coupling j
Natural product synthesis
1. Introduction
There is no biocatalyst known to date that incorporates a
noble metal;1 it would have been a significant evolutionary
handicap if any such scarce element were indispensable for life.
Although the boundary conditions for chemical synthesis, as
practiced by mankind since the advent of the industrial age, are
certainly much different, it is arguably relevant to contemplate
how metalloenzymes are able to effect so many different
chemistries with breathtaking ease even though they rely on
base metals only. Can their chemical properties be emulated in
industrially viable settings? Can the range of transformations
even be extended beyond the repertoire of nature? The scien-
tific community worldwide is well aware of these and related
has massively grown and become a mega-trend in recent years.2
This important development notwithstanding, it is fair to say
that the dominance of the noble metals over large parts of
homogeneous catalysis has not yet been challenged to the
extent one might expect.3
This conclusion may seem perplexing at first sight since
almost all noble metals are not just expensive but subject to
“political” price fixing as a consequence of their uneven global
distribution; the supply is un-sustained on the longer run, and
their physiological and toxicological properties are not partic-
ularly favorable either. These ® a priori ® significant draw-
backs are obviously outweighed by a number of most attractive
chemical attributes: the quest for truly competitive base metal
catalysts must therefore start by asking what these virtues of
the noble metals are and how they can be mimicked by cata-
lysts based on iron and its neighbors from the fourth period
of the transition metals. Short such analyses have been pub-
lished and are not reiterated here.4,5 Rather, the present Account
outlines how the iron catalysis project in my laboratory has
started with the ambition to emulate conventional cross
coupling chemistry, but has evolved since then into a search
for new reactivity.
2. Canonical Cross Coupling
The overwhelming success of palladium catalyzed C­C and
C­X bond forming reactions may hide the fact that the term

666 | Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319 © 2021 The Chemical Society of Japan
“cross coupling” had originally been coined in the context of
iron catalysis. It was used in Kochi’s pioneering reports on
reactions of certain Grignard reagents with alkenyl halides in
the presence of simple iron salts;6 the first publications of this
series pre-date the seminal discoveries of nickel- and palladium
cross coupling that triggered the avalanche shortly thereafter.7
Interestingly enough, scattered examples of what would nowa-
days certainly be called iron catalyzed “homo coupling” and
“cross coupling” had already been published prior to Kochi’s
work, although the impact was arguably marginal.8
The potential advantages notwithstanding, the scope of early
iron catalyzed cross coupling was narrow. Largely variable
outcomes were recorded even for alkenyl halides,6,9 and only
few other types of electrophiles were found suitable.10 This
limitation was perhaps a major reason for a “latency period”
with little activity in the field, which lasted nearly until the turn
of the millennium. Only at this point in time was the field
thoroughly revisited: several independent reports showcased
that the potential of iron catalysis for C­C-bond formation in
general and cross coupling in particular had been largely
underestimated.11­14
Our group’s first systematic foray pursued the simple but
important goal of extending iron catalyzed cross coupling to
aryl halides. Though arguably the most important type of elec-
trophiles, they had neither been addressed by Kochi nor anyone
else prior to our work. Gratifyingly, many aryl chlorides,
-triflates and even -tosylates were found to react well with
Grignard reagents in the presence of iron salts as simple as
Fe(acac)3 (Scheme 1).14 External ligands can be used but are
not mandatory, whereas co-solvents or additives such as N-
methylpyrrolidone (NMP) or TMEDA usually prove advanta-
geous; they are believed to control the speciation in solution,
even though their exact role is hardly understood at the molec-
ular level.15 NMP was later classified as potentially reprotoxic,
but many benign alternatives of similar efficacy were found
since.16
Several lines of evidence prove that it is the iron that
accounts for the cross coupling and not trace impurities in the
precatalyst (Cu, Pd etc.).17 Specifically: (i) iron salts of the
highest available purity show unchanged performance; (ii) aryl
chlorides are typically much better substrates than the corre-
sponding bromides or iodides,14 very much opposite to what is
observed with copper- or palladium catalysts; (iii) the reactions
proceed with unprecedented rates at temperatures as low as
¹78 °C in some cases, at which copper or palladium catalysts
usually fail to activate aryl chlorides; (iv) structurally well-
defined and fully characterized iron complexes were found that
are even better (pre)catalysts than simple iron salts.
Because several excellent reviews on this topic are available,
a summary in “al fresco” style may suffice at this point.18­23 In
the original format, alkylmagnesium halides proved to be the
n-Hexyl-MgBr O N
O
Fe(acac)3 (5 mol%) OMe
OMe
Cl THF/NMP, 0°C, <10 min
1 2
84% [15 g scale]
Scheme 1. Prototypical iron catalyzed aryl/alkyl coupling
reaction.
Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319
reagents of choice.14 Many reactions proceed with excep-
tionally high rates at or (much) below room temperature.
Because of this favorable kinetic profile, various functional
groups remain untouched, which one would expect to react
with Grignard reagents otherwise. Electron deficient aryl- or
heteroaryl chlorides are the most adequate substrates, whereas
triflates are typically required as the leaving group in case of
electron-rich reaction partners. Unfortunately, the analogous
aryl-aryl coupling turned out to be of limited scope;14 since the
original report, however, much progress has been achieved in
this important field, even though a completely general proce-
dure is still awaited.24
For the many favorable attributes, iron catalyzed aryl/alkyl
cross coupling was rapidly embraced by the community and its
scope was further extended: for example, many additional and
rather “unconventional” leaving groups proved viable, which
traditional palladium catalysts fail to activate (aryl sulfamates,
carbamates, carboxylates, phosphonates, (thio)ethers, trialkyl-
ammonium salts etc.).18­23 Moreover, certain nucleophiles
other than Grignard reagents can be used, even though there
is room for further improvement.12,18­23 Applications to natural
product synthesis corroborate the utility of this chemistry.25
This notion is exemplified by the serial cross-coupling of the
bifunctional pyridine derivative 3 with two different Grignard
reagents in one pot (Scheme 2); the resulting product 5 was
then swiftly transformed into muscopyridine by a one-pot ring
closing metathesis/hydrogenation cascade.26,27 Since iron
catalyzed cross coupling reactions scale well,28 several appli-
cations from industrial laboratories to various bioactive com-
pounds have already been disclosed (Figure 1).29,30
In view of the foregoing, it may not come as a surprise
that we found other electrophiles such as alkenyl triflates
(­tosylates) or acid chlorides to be well-behaved reaction part-
ners too;31 many additional types of substrates were added to
the list by other research groups.18­23 Once again, a growing
number of applications to natural product synthesis bears
witness to the power of this chemistry. The straightforward
synthesis of cubebene by a sequence of π-acid catalyzed
cycloisomerization of an enyne with concomitant 1,2-acyl
shift32 followed by an iron catalyzed cross coupling is repre-
sentative (Scheme 3).25,33­36
3. Steps Beyond the Canon: Alkyl Electrophiles
Where applicable, iron catalysis has notable merits for being
fast, productive, mild, benign and cost-effective. From a con-
ceptual perspective, however, the transformations described in
BrMg
Cl N 4
MgBr
Cl N OTf Fe-salene (5 mol%)
80%
3 THF/NMP, 0°C 4
N Muscopyridine
5
Scheme 2. Sequential “one-pot” cross coupling en route to
muscopyridine.
© 2021 The Chemical Society of Japan | 667
 O CF3 O OMe
HO N N Ph2 Zn(tmeda) 2MgX2
O Br O
AcO [L FeCl 2] (3 mol% AcO Ar2 P PAr2
N
56 g scale 210 g scale AcO OAc THF, 0°C AcO OAc Ar = 3,5(TMS)C6H3-
@ 0.1% Fe loading @ 0.1% Fe loading 9 x 245 g scale 2 kg scale OAc 96%, / = 73:27 OAc L = TMS-SciOPP
NBn2 10 11
N N(PMB)2
N N H
N N OTES OTES
Br N F3C MgBr
N
O OBn O OBn
3.8 kg scale MeO MeO
2.9 kg scale 6.9 kg scale
O OTES O OTES
FeCl 3 (10 mol%)
F3C MeO tmeda, THF
I
O
84%
OTES 12 OTES 13
O O NMe2

0.8 - 60 kg scale 6 x 50 kg scale

Me
P P
Figure 1. Larger-scale applications of iron catalyzed cross Me
O
MgBr (6 mol%)
coupling reactions of alkenyl-X and aryl-X derivatives. Cl
O
+ Fe(acac)3 (3 mol%) O
O
THF, 0°C
MeMgBr rac- 14 15 (82%, er = 90:10)
AcO PtCl2 (2 mol%) Fe(acac)3 (10 mol%)

92% H Scheme 4. Examples of advanced “inverse” alkyl/aryl cou-

H THF, -30°C Me
RO H
90%
H
pling reactions from the literature.40h,42,43
6 7 R = Ac α-cubebene (9)
8 R = OTf MesMgBr
Et2 Cl Et 2
depe (2.5 eq.) P P (2.2 eq.) Et 2 P PEt 2
Me FeCl2(THF)1.2 Fe
Me Fe
OTBS THF, RT P P THF, 70°C
H H Et2 Cl Et2
MOMO OTBS O H Mes Mes
88% 81%
Me H O O 16 17
O
Ph O
O O O
O H H H H OTBS
72% O 2,5-Me2C6H3MgBr (vycor filter)
H
95% TBSO
O 89% I cyclohexane
17 (5 mol%), THF, 70°C
18 73% 19
Scheme 3. Examples of iron catalyzed cross coupling reac-
tions of alkenyl triflates as applied to natural product
H retigeranic acid
synthesis. H
H
HO
20 21 O
the previous Section replicate no more than a small subset of
cross coupling reactions which palladium is perfectly able to Scheme 5. Iron catalyzed coupling of a sterically hindered
effect. Grignard reagent: formal synthesis of retigeranic acid.
During our initial studies, however, we became increasingly
aware that there is an orthogonal agenda in that iron catalysts as mesitylmagnesium bromide, which are low-yielding other-
are also capable of promoting transformations (largely) beyond wise.44,45 The straightforward preparation of 19 illustrates this
reach of their noble cousins. A first step in this direction was aspect (Scheme 5): this particular product had previously served
taken when we learned that aryl-Grignard reagents react as substrate of an elegant total synthesis of retigeranic acid and
exceedingly well with alkyl halides as electrophilic partners. silphiperfol-6-ene via alkene/arene meta-photocycloaddition as
In our case, this discovery was made during investigations into the key step.46
the reactivity of structurally well-defined low-valent iron com- The net propargylic substitution observed in reactions of 1-
plexes (see below).37 At the same time, other research groups alkynylcyclopropyl tosylates with alkylmagnesium halides and
had made similar observations using much simpler and hence catalytic Fe(acac)3 is deemed another noteworthy advance
more practical catalyst systems.38,39 (Scheme 6). It represents the first example of successful cross
Since then, this “inverse” alkyl/aryl coupling has become coupling of a tertiary alkyl electrophile under iron catalysis.47
a focal point of research activities, and important advances The method was used in the context of natural product chem-
were reached in preparative as well as mechanistic terms istry and the resulting structural motif is present in a number of
(Scheme 4).40,41 Somehow reciprocal to what had been found bioactive ingredients too.48,49
in reactions with aryl chlorides, the coupling of alkyl halides To properly assess this result, one has to keep in mind that a
often benefits from the use of ancillary ligands. This fact pro- variety of other propargylic substrates undergoes vinylogous
vides opportunities for fine-tuning and for asymmetric catalysis substitution with formation of the corresponding allenes.50­54
as well. The example of the racemic α-chloropropionate 14 that Such transformations allow stereochemical information to be
is converted in an enantioconvergent manner into optically relayed from a stereogenic center to a chiral axis. In view of the
active 15 is a landmark.42 high reactivity of allenes, this information content can be used
Ligand-tuning allowed yet another limitation to be over- in many different ways, as illustrated by the formation of the
come: complex 16, for example, endowed with commercially tetrasubstituted chiral center of the tetrahydrofuran derivative
available bis(diethylphosphino)ethane (depe) is able to cata- 28 (Scheme 7).55 Specifically, propargyl epoxide 26 was treat-
lyze cross coupling reactions of Grignard reagents as hindered ed with n-PrMgCl in the presence of catalytic Fe(acac)3 to

668 | Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319 © 2021 The Chemical Society of Japan
 MeMgCl
OTs MeLi
Fe(acac)3 (5 mol%) Me
MeLi TBSO O TBSO O
TBSO O
THF, -20°C Fe(acac) 3 cat.
Cl Me
70% X [M] [M]
Ph 22 Ph 23
29 X = O CCl 4, PPh3 C
B
30 X = CCl2 70%
MgBr OH
OTs H O
Fe(acac)3 (5 mol%)
OH O
TBSO HO
THF, -20°C 75%
H
SiMe3 24 92% SiMe3 25 31 Brefeldin A

Scheme 6. Cross coupling at tertiary propargylic centers. 47,48 Scheme 8. Iron catalyzed synthesis of internal alkynes;
application to the total synthesis of brefeldin A.
n-PrMgBr RO
RO [M] RO OH
Fe(acac) 3 cat. O
O
R = TBDPS E
Me [Fe]
MeMgBr O O[M]
Me
26 A 27 (62%, syn:anti = 8:1)
[M] COOH
O O Fe(acac)3 cat. O O Me
F
O -30°C, 93%
32 D O O 33 (dr > 20:1)
Me
AgNO3 RO O HO O
CaCO3
HO O
O Scheme 9. Iron catalyzed formal ring opening/cross
90% coupling.
28 Amphidinolide Y

Scheme 7. Iron catalyzed allene synthesis by opening of a
propargyl epoxide; application to the total synthesis of
amphidinolide Y.
furnish allenol 27 in less than five minutes reaction time. The
fact that the syn-isomer was formed preferentially (dr = 8:1) is
thought to reflect a “directed delivery” of the nucleophile via
pre-coordination (A) of the (loaded) oxophilic iron catalyst to
the epoxide O-atom; for this stereochemical course, the reac-
tion is complementary to the anti-selective opening of propar-
gyl epoxides with organocopper reagents. The axial chirality of
27 was then transmitted to the tertiary ether center upon acti-
vation of the allene with the aid of a carbophilic Lewis acid.56
The resulting product 28 served as key building block for the
total syntheses of amphidinolide X and Y.55,57,58
4. Internal Alkynes Derived from Lactones
Because of their activated carbonyl character, many lactones
are amenable to Wittig-type olefination, which ordinary esters
do not undergo. This propensity can be used to access gem-
dichloro olefin derivatives such as 30.59 On treatment with
lithium sand, these compounds afford the corresponding
terminal alkynes.60 We saw an opportunity to extend the scope
and reach internal alkynes simply upon replacement of lithium
by organolithium reagents RLi.61
The desired reaction takes place even in the absence of a
catalyst, but it is much accelerated by either copper or iron
salts; in the latter case, a mixture of Fe(acac)3 and 1,2-
diaminobenzene proved optimal.62 This variant works partic-
ularly well for exo-dichloroolefins derived from five-membered
lactones (Scheme 8). The catalyst likely promotes the initial
metal/halogen exchange with formation of a metal vinylidene;
intermediates of type B are known to be electrophilic63 and
capable of intercepting a second equivalent of RLi to give C
prior to reductive elimination.62 Note that the substituent R
attached to the triple bond is derived from the nucleophile,
which distinguishes this transformation from a classical Corey-
Fuchs alkynylation/alkylation sequence.64
The new entry into non-terminal alkynes has served natural
product synthesis well. Whereas the copper-catalyzed proce-
dure furnished key building blocks for our recent total syn-
theses of tulearin A and C,61,62 kendomycin,65 and 5,6-
dihydrocineromycin B,66 the iron-catalyzed variant proved
instrumental for our approaches to callyspongiolide67 and
brefeldin A (Scheme 8);68 all of these projects relied on ring
closing alkyne metathesis (RCAM) as an exquisite means to
forge macrocyclic frameworks.69,70 The reactions were per-
formed on multigram scale and show that chiral centers α to the
former lactone carbonyl remain intact.
5. Iron-Catalyzed Ring-Opening/Cross Coupling
In recognition of the fact that different types of alkenyl elec-
trophiles are amenable to iron catalyzed cross coupling, we
explored whether compounds comprising such a motif as part
of a heterocyclic ring react analogously. 2-Pyrones fall into this
category, not least because they show little aromatic character
and can be viewed as cyclic enol ester derivatives.
In line with this notion, treatment of 32 with MeMgBr and
catalytic amounts of Fe(acac)3 in toluene or Et2O at low temper-
ature furnished acid 33 in good yield and excellent selectivity
(Scheme 9).71 For its “non-thermodynamic” Z,E-configuration,
the product is highly isomerization-prone; actually, it sufficed
to warm the mixture to ambient temperature prior to work-up
to transform the kinetic product into the more stable E,E-
isomer.71 To the best of our knowledge, this kind of formal “ring
opening/cross coupling” of pyrones has no precedent in palla-
dium catalysis; it is enabling in that it provides access to
highly substituted di-unsaturated acid derivatives that are
difficult to make otherwise.
From the conceptual viewpoint, this transformation marks a
new frontier for cross coupling in general, because the former
“leaving group” is retained as an integral part of the result-
ing product. Moreover, it shows that heterocycles may be an
underutilized pool of substrates that deserves more attention.
Because of the exceptionally mild conditions, it was hoped
that pyrone ring opening/cross coupling would be applicable

Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319 © 2021 The Chemical Society of Japan | 669
 S S
OPMB
N N
OTBDPS
MeMgBr
BocHN Fe(acac)3 (30 mol%) BocHN
73% (97% brsm)
O O
O O O O
34
S S
OPMB
N N
O O
O O
BocHN H2N
O O
O 36 O
Scheme 10. Iron catalyzed pyrone ring opening/cross cou-
pling as the key step of a total synthesis of pateamin A.
to more elaborate substrates comprising functionality that
might not subsist to a Grignard reagent otherwise. The marine
macrolide pateamin A72 and the synthetic analogue desmethyl-
desamino-pateamine A (DMDA-Pat A)73 were identified as a
particularly relevant testing ground. These potently cytotoxic
compounds exhibit differential activity in xenograft melanoma
models in vivo.74 Moreover, pateamin A is the only potential
lead compound known to date which shows activity against
cachexia, a muscle wasting syndrome that often takes a lethal
course with immunosuppressed or cancer patients. Moreover,
it is a very valuable probe molecule for chemical biology as
it brings protein biosynthesis to a hold by blocking the initial
translation steps; its target protein is the eukaryotic initiation
factor 4A.74
Since pateamin A derives from a marine sponge, it is in
extremely short supply. A total synthesis that is “scalable” to
the extent that it allows in-depth biological and pharmacolog-
ical profiling of this lead compound to be carried out meets a
real demand. Any such project faces several difficulties, but the
formation of the non-thermodynamic Z,E-dienoate spanning
the macrodiolide ring is critical because the integrity of this
substructure is innately linked to the biological activity of the
compound.
We were pleased to learn that a sequence of gold catalyzed
pyrone formation, which was developed in our laboratory in
parallel work,75,76 followed by iron catalyzed pyrone opening
served the purpose very well (Scheme 10). Thus, treatment of
the N-Boc protected derivative 34 with excess MeMgBr and
Fe(acac)3 (30 mol%) at ¹60 °C furnished the desired product
35 in 79% yield (97% brsm) with an isomer ratio of ²17:1.77
This example illustrates the compatibility of the reaction with
various electrophilic substituents as well as its insensitivity vis-
à-vis the donor sites of the adjacent thiazole. Since the reaction
directly furnished the free acid after work-up, the further
elaboration into the desired macrocycle 36 by subsequent
lactonization was greatly facilitated and the risk of epimeriza-
tion minimized. Product 36 thus formed then paved the way to
pateamin A.77
The strategy to encode the isomerization-prone Z,E-
configured dienoate in the form of a robust heterocycle, from
which it is revealed only at late stage, paid valuable dividends
in that it rendered the overall synthesis short, robust and pro-
ductive.77 The fact that iron catalysis does not only unmask the
670 | Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319
OPMB
OTBDPS (CO)3Fe
HOOC Ph
O O O O
37
22
Me
35
NMe 2
Pateamin A
Figure 2. Structure of a model complex in the solid state.77
dienoate but concomitantly installs the methyl branch at C22
provides opportunities to explore structure/activity relation-
ships by using nucleophiles other than MeMgBr. Moreover the
underlying synthesis blueprint also brought the sister com-
pound DMDA Pat A into reach.78
An important aspect yet to be discussed is the mechanism
of this new formal ring opening/cross coupling manifold. The
fact that the R group delivered by the Grignard reagent replaces
the ester leaving group with retention of configuration of the
enol double bond corresponds to the pattern of a true cross
coupling process (Scheme 9). Much evidence, however, speaks
against a canonical course, in which the iron catalyst ® before
or after reaction with the Grignard reagent ® would oxidatively
insert into the C­O bond. Rather, it is thought that the reaction
proceeds via π-complex formation (D) followed by delivery of
the nucleophile in what is best described as a 1,6-addition
reaction (Scheme 9).71,77 This proposal gains credence from the
fact that iron catalyzed 1,6-additons to dienoates and related
substrates are known to be facile.79 Finally, the resulting
enolate of type E (or F) succumbs either to a torquoselective
electrocyclic ring-opening or is broken via an ionic mechanism.
Although no intermediate could be characterized in situ or
ex situ, the structure of the model iron carbonyl complex 37
is deemed informative (Figure 2):77 it shows the purported η4-
binding of the metal fragment to the pyrone π-system. Substan-
tial back-bonding from iron into the antibonding orbitals of the
ligand entails re-hybridization and forces the heterocyclic ring
to bend; as a result, orbital overlap between oxygen and the
double bond is disrupted and the enol ester character largely
lost. Equally if not more important is the fact that C5, as the
center to which the nucleophile will be delivered, gains signif-
icant “carbenoid” character in that it carries a carbon-metal
bond and a leaving group. The electron back-donation referred
to above alters the bond lengths throughout the ring: most
notably, the C3­C4 bond is shortened as if it “anticipates” the
bonding situation of the 1,6-addition product to be formed as a
transient intermediate prior to ring opening. Collectively, these
structural features are thought to render delivery of the R-group
of RMgX to C5 not only possible but actually facile, very
much in line with what is experimentally observed.71,77
Whether the subsequent ring opening of the resulting enolate
proceeds in an electrocyclic or ionic manner remains unclear at
this point; indirect evidence speaks for the latter mechanism.77
This mechanistic picture is consistent with additional data
from the 2-pyridone series (Scheme 11).80 For the poorer leav-
© 2021 The Chemical Society of Japan
 PhMgBr E E
Fe(acac)3 (5 mol%) PhMgBr
Et2O, -30°C Fe(acac)3 (5 mol%)
[Fe]
Ph O NHTs then DMF N O Ph N O
THF, -45°C E E
R Bn R E E E
R = Ts, 60% R = Bn, 96%
40 38 39 G E
[CpFe(ethylene)2]Li

Scheme 11. Iron catalyzed 1,6-addition versus formal ring R

cat.
E E
C
[Fe] R
opening/cross coupling. 45 42
E
E
R
[Fe]
42
67% ([4+2])
H

E E Scheme 13. The iron catalyzed [4+2] cycloaddition com-

E E mences at the enyne rather than the diene subunit.

E E
E E
lary alkenes by the substrate, followed by oxidative cyclization
Ph
[CpFe(olefin)2]Li with formation of the corresponding metallacycles which then
Ph E E E = COOEt
E E
Ph evolve into the observed products. For the Alder-ene reaction,
41 43 detailed labelling studies allowed conceivable alternative sce-
75% ([5+2]) 95% (Alder-ene)
narios to be ruled out (allylic C­H activation or metal hydride
Ph

E
addition/Heck reaction pathway).86 In the case of the metal-
E
E E catalyzed Diels-Alder cycloaddition, it is not intuitive whether
E 44
a substrate of type 45 initially forms a metallacycle G derived
E 89% ([2+2+2]) from the 1,3-diene entity, into which the alkyne then inserts;
45 could also behave as an enyne in the first place, that gives
Scheme 12. Prototypical cycloaddition and cycloisomeri-
rise to a metallacycle H which expands to give the final product
zation reactions catalyzed by CpFe(0) complexes.
(Scheme 13). Control experiments showed that 1,3-butadiene
ing group properties of an amide, it was possible to intercept is incapable of replacing the ethylene ligands of [CpFe-
and isolate 1,6-addition products such as 39. Upon activation of (alkene)2]Li, which in turn suggests that a pathway via G is
the 2-pyridone by N-tosylation, formal ring opening/cross cou- unlikely to be operative; rather, the alkyne is needed for the
pling with formation of 40 takes over, as one might expect.80 reaction to take place.89

6. Iron Catalyzed Cycloisomerization 7. Vignette: Perplexing Redox Events

and Cycloaddition Reactions
The ability of low-valent iron to ligate π-bonds of all sorts is
textbook knowledge;81,82 the affinity to alkynes and 1,3-dienes
is particularly high. Therefore, and in consideration of some
early literature precedent,83 it seemed likely that iron cata-
lysts are able to promote various types of cycloaddition and
cycloisomerization reactions known from the realm of noble
metal catalysis otherwise.84
Complexes of type [CpFe(alkene)2]Li, which were used at
the outset of our investigations, are readily formed on scale
from ferrocene by reductive cleavage of one cyclopentadienyl
ring in the presence of either ethylene or 1,5-cyclooctadiene
(COD) (see below).85 As can be deduced from the structure in
the solid state, the very electron-rich, formally zero-valent iron
center is strongly engaged with the π*-orbitals of the ligand
through electron back-donation, even though the olefins remain
kinetically labile.86 These properties readily explain why such
complexes catalyze [4+2], [5+2] and [2+2+2] cycloaddition
as well as Alder-ene reactions of appropriate substrates
(Scheme 12);86,87 a number of reducible functional groups,
basic sites and C­H acidic terminal alkynes are tolerated. It is
of particular note in the present context that these types of
transformations had originally been developed with noble
metal catalysts;84 our results prove that low-valent iron is a
serious alternative.88
Compelling evidence suggests that the reactions catalyzed
by [CpFe(alkene)2]Li commence by exchange of the ancil-
As mentioned above, CpFe(0) complexes such as 43 and
44 originally used in our laboratory to study iron catalyzed
cycloisomerization and cycloaddition chemistry are formed on
treatment of ferrocene (Cp2Fe) with lithium in the presence of
the appropriate olefin (Scheme 14).85,86 Under slightly more
forcing conditions, both Cp-rings of Cp2Fe are reductively
cleaved off, leading to the formation of the tetraethylene ferrate
complex 45 or the analogous complex 46, each comprising an
iron center of the formal oxidation state ¹2 and a formal d10
electron count.85,90 As such, they are cousins of Collman’s rea-
gent Na2[Fe(CO)4];91 for the much more labile ligand sphere,
however, they are inherently more reactive.
Though obviously very sensitive to air and moisture, such
“exotic” complexes are routinely made on º10 g scale from
cheap starting materials and therefore provide a unique plat-
form for the study of “ultra-low-valent” iron.86,90 Iron species
of formally negative oxidation states were originally thought to
play a key role in cross coupling,14 because Grignard reagents
had previously been reported to transform iron salts into such
highly reduced entities.92 Although later (spectroscopic) results
speak against a systematic involvement,93 it remains a matter of
fact that 45 and 46 are perhaps the most active catalysts for
various iron catalyzed C­C bond forming reactions known to
date.37,90
Reduction of FeX2 ligated to phosphine ligands with lithium
under ethylene atmosphere takes a more conventional course in
that it stops at the Fe(0) stage. In our hands, the use of EtMgBr

Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319 © 2021 The Chemical Society of Japan | 671
 [M]
Fe(acac)3
(tmeda)Li Fe Li(tmeda) X X
RMgX
45 [Fe] K H L
X [Fe] X
Li, ethylene, (5 atm) H
43% H
RT, then tmeda
RMgX
[Fe] XMgX
MgX
I X
Li, cod Li, ethylene (1 atm) J
Li (dme) Li (tmeda)
Fe Cp2Fe Fe
DME, -50°C to RT -50°C to 0°C [Fe] R
44 43 [M]
97% then tmeda, 45% M N
R

22% Li, ethylene, (5 atm)

DME, then cod, 70°C
Scheme 16. A novel cycloisomerization/cross coupling
cascade, merging bond-forming and bond-breaking events.
[(cod)2Fe] [Li(dme)]2 (46)
OH
O MgX
Scheme 14. Formation of low-valent iron complexes from COOMe COOMe

ferrocene. [Fe(acac)3] cat.

Cl
R Fe EtMgBr (excess)
P Cl P two C-C-bonds are formed
P R
R ethylene, THF, -5°C R one C-C-bond is broken!
R R
47 R = iPr 77-97%
48
C6H11 MgCl (excess) +4
Fe
FeCl 2
THF, -35°C
20-25% (+ [Fe] colloid]
Scheme 15. The strikingly different outcome of reactions of
iron salts with Grignard reagents bearing β-hydrogen
atoms.
instead of the alkali metal proved much more reliable.94 The
reduction of 47 to 48 on (multi)gram-scale is representative
(Scheme 15). This well-characterized complex constitutes
another valuable starting point for forays into the underex-
plored organometallic chemistry of low-valent iron.89,94
To illustrate the intricacies that one may encounter, reference
is made to the seemingly analogous reaction of FeCl2 with
cyclohexylmagnesium chloride, which leads to a completely
different outcome: [Fe(C6H11)4] (49) was the only defined prod-
uct that could be isolated from the mixture (Scheme 15).95 This
complex represents an extremely scarce example of a homo-
leptic Fe(+4) species; it is diamagnetic (!) despite the tetra-
hedral ligand environment. The formation of 49 can only be
explained by disproportionation of an Fe(+2) intermediate,
with formation of colloidal iron as the second product.95 The
meta-stability of 49 is perplexing since the central iron atom is
surrounded by ligands bearing no less than 20 H-atoms amena-
ble to α- or β-hydride elimination. In any case, the comparison
shown in Scheme 15 illustrates that extrapolations from one
reaction to a seemingly similar reaction can be misleading. This
conclusion, in turn, implies that our knowledge of some of the
rather basic chemistry of iron is still in its infancy.
8. Merging Iron Catalyzed Cycloisomerization
and Cross Coupling
As outlined above, all available evidence speaks for the
intervention of ferracycles as key intermediates in the cyclo-
addition and cycloisomerization reactions shown in
Schemes 12 and 13. In consideration thereof, we envisaged a
conceptually new reaction manifold based on unprecedented
Me
Me THF, -30°C 51
50
90%, E/Z > 99:1
R Fe0
E
P R E E BrMg O
O E
COOMe
COOMe
Fe(acac)3 cat. O
63%, E:Z > 98:2
52 53 O
E = COOMe
Scheme 17. Iron catalyzed cycloisomerization/cross
49
coupling.
bond-breaking/bond-making events downstream of metalla-
cycle formation.96
Specifically, placement of a potential leaving group X next
to the alkene as shown in I might give ring opening a chance to
outperform β-hydride elimination because of the favorable
alignment of the C­X σ*-antibonding orbital with the electron-
rich C­M bond within the emerging rigid bicycle J
(Scheme 16). However, such a bond-breaking event does not
regenerate a catalytically active low-valent metal species in the
way β-hydride elimination ultimately would (J¼K¼L); there-
fore the envisaged ring opening step must be juxtaposed with
an alternative process that regenerates the active catalyst and
ensures turn-over.
Apprehensive of the tendency of (low-valent) iron to form
ate-complexes on exposure to Grignard reagents or related
nucleophiles (see the next Vignette), we planned to make use of
cross coupling for this very purpose.96 If a “loaded” iron spe-
cies M transfers the R-group to the emerging product N, the
reductive bond formation should adjust the oxidation state and
hence close a catalytic cycle. At the same time, the Mg(+2)
cation might assist the overall process by lowering the barriers
upon coordination to the (heteroatom) leaving group X in-
scribed into the frame of M.
The conceived scenario was reduced to practice with the
aid of structurally well-defined iron complexes but also with
iron catalysts generated in situ from Fe(acac)3 and Grignard
reagents (Scheme 17).96 Unsurprising perhaps in view of the
results previously obtained with iron catalyzed canonical cross
coupling,14 alkylmagnesium halides perform better than their
aromatic siblings. They afford functionalized 1,3-diene prod-
ucts such as 51 comprising stereodefined tetrasubstituted
alkenes in good yields and generally excellent selectivity.96
Not only heteroatoms were found to be suitable leaving groups;

672 | Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319 © 2021 The Chemical Society of Japan
rather, the malonate derivative 52 proves that even activated C­
C-bonds can be cleaved by this catalytic process: in the case of
product 53, two new C­C bonds were formed while one C­C
bond was concomitantly broken during this unorthodox cyclo-
isomerization process.96
It is appropriate to mention here that palladium catalysts
can serve similar purposes. Actually, they allow aryl groups to
be transferred, which the iron-based system does not do well.
What is remarkable though is the fact that iron catalysis
proceeds rapidly at ¹30 °C, whereas the palladium catalyzed
reactions mandate heating to +90 °C.96 This differential illus-
trates the exceptional driving force pooled in the iron catalyst,
which might well be harnessed in other settings too.
9. Vignette: Iron Ate-Complexes
Early observations suggested that reactions of iron salts with
higher alkyl-Grignard reagents lead to the formation of low-
valent iron complexes by β-hydride elimination reactions
and/or reductive coupling processes (compare complex 48,
Scheme 15).14,31 In contrast, nucleophiles that cannot undergo
either reduction mechanism were supposed to furnish iron-ate
complexes in analogy to the well-known cuprates invoked in
much of organocopper chemistry.14,31
The first such ferrate species that was shown to be relevant in
the context of iron cross coupling was a “super-ate” complex
formed on reaction of FeCl2 with excess MeLi.97 The resulting
homoleptic species [(Me4Fe)(MeLi)][Li¢(OEt2)]2 (54) carries
four methyl groups in a tetrahedral arrangement about the
Fe(+2) center (Figure 3); three of them entertain additional
contacts to three escorting lithium counterions, which form a
tetrahedral metal framework with the iron center. Strikingly
though, the cluster incorporates a fifth methyl group (C5)
devoid of any direct interaction with the iron atom.90,97 This
unusual complex proved competent, inter alia, for the alkyla-
tion of alkenyl halides, alkenyl triflates, and acid chlorides, as
well as for pyrone ring opening/cross coupling.71,90 PhLi
afforded the related ate-complex [Ph4Fe][Li¢(OEt2)2][Li¢(1,4-
dioxane)], even though it lacks a fifth RLi entity.90 In con-
trast, more bulky aryl-Grignard reagents give “ordinary” ate-
complexes of type [Ar3Fe]¹ carrying a single negative charge
Figure 3. Structure of the dianionic “super-ate” complex
[(Me4Fe)(MeLi)][Li¢(OEt2)]2 (54) in the solid state;97 note
that only C1, C2, C3 and C4 are bound to the Fe(+2)
center, whereas C5 has no direct contact; this additional
MeLi “ligand” likely serves to complete a stable tetra-
hedral metal core comprised of Li1, Li2, Li3 and Fe1.
Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319
and only three organic residues in the first coordination
sphere.44,98
More recent studies using advanced spectroscopies to study
freeze-trapped intermediates generated in situ confirmed the
intervention of ate-complexes in several iron catalyzed C­C-
bond forming processes. Moreover, it has been convincingly
shown that ate-complexes are subject to facile ligand exchange
and evolve with time to lower oxidation states.99 They can
undergo either two-electron reduction with formation of Fe(0)
or single-electron reduction with formation of Fe(+1). Strik-
ingly, the latter process is neither the result of homolytic cleav-
age or disproportionation, as one might tend to think, but rather
a consequence of the transient formation of dinuclear entities,
which must be accessible on steric ground for the reaction to
proceed. This insight illustrates the intricacy of this chemistry
and arguably provides guidance for future catalyst design.99,100
A particular highlight is the study into the ferrate species
formed on treatment of FeX3 with excess RMgBr (R = Me, Et).
In the absence of NMP, ferrate cluster species of the formal
composition [R12Fe8][MgCl(thf )] are generated;101,102 in the
presence of NMP, in contrast, [R3Fe][Mg(nmp)6] is formed
in situ (even in case of R = Et, where β-hydide elimination is
expected to take place).15,103 These latter complexes almost
certainly represent the reactive intermediates accountable for
the seminal results described by Kochi and coworkers on the
iron catalyzed cross coupling of alkenyl halides.6 One must
appreciate the difficulty in characterizing reactive complexes of
this level of complexity, which are extremely air- and moisture
sensitive, and, in case of [R12Fe8][MgCl(thf )], also paramag-
netic. This formidable “analytical frontier”4 is a major hurdle
and the progress in the understanding of iron catalysis achieved
in recent year therefore all the more impressive.
10. A Case Study in C­H Activation
Base metal catalysts in general and iron catalysts in par-
ticular show great promise in C­H activation reactions.104­106
As this topic is beyond the scope of the present Account, a
single case study must suffice to illustrate the point. Specif-
ically, ligand exchange between the Fe(0) ethylene complex 48
with 1,3-cyclohexadiene takes a rather intricate course in that
it leads to the clean formation of 55 (Scheme 18).89,94 This
outcome is best rationalized by assuming that replacement of
one ethylene ligand by the diene is followed by instant acti-
vation of the allylic C­H bond. Migratory insertion of the
remaining ethylene into the iron hydride transiently formed
gives an iron ethyl intermediate; reductive ligand coupling
R Fe P R P R
P R P Fe H R P Fe H
P R R R R R
R
R 48
R Fe R
Fe
P P R
P R P R
H
P
Fe
H
R
R
R P R 55
R R
R
Scheme 18. Iron-mediated allylic C-H activation/coupling
cascade.
© 2021 The Chemical Society of Japan | 673
entails C­C bond formation and regenerates a low-valent iron
center poised for the next C­H activation event that forms the
final product 55.89,94 The endo-orientation of the ethyl sub-
stituent in 55, which was ascertained by X-ray diffraction,
supports this involved mechanistic scenario.
The elementary steps underlying the cascade comprised of
two consecutive C­H activation events and an interwoven
stereoselective C­C-bond forming step are deemed enabling:
the overall reaction can also be seen as the prototype of an
unconventional “cross coupling” process employing cheap
ethylene as pre-nucleophile in lieu of a preformed organo-
metallic reagent.
11. Conclusion
This personal Account article does not provide a compre-
hensive treatise of iron catalyzed C­C bond formation. Rather
it is meant to showcase that the use of this base metal (and its
neighbors from the fourth period) provides valuable oppor-
tunities in “conventional” cross coupling; at the same time, it
opens intriguing perspectives for the discovery of genuinely
novel transformations.
The awareness that sustained catalysis mandates the devel-
opment of systems operating with base metals in general and
iron in particular is rapidly increasing. Yet, the understanding
of many of their fundamental properties lags behind: What are
the best ways to characterize fleeting paramagnetic intermedi-
ates?41,107 Where and how does the spin-state come into play
and where does spin crossover intervene (“two-state reactiv-
ity”)?108­110 How can ligands be designed that allow the spin-
state to be controlled? Will a given complex favor single-
electron or two-electron transfer?111 In which cases is dispro-
portionation a shortcut for “regular” redox events? How can
“non-innocent” ligands and/or other metal/ligand cooperativ-
ity be used to advantage?112,113
Certain answers to these and related questions can be found
in the pertinent literature, but a fully comprehensive picture
does not emerge from the current state-of-the-art; some of the
examples discussed above corroborate this notion. Although
the challenges in this field of research are tremendous, the
ingenuity of the next generation of scientists is certainly up to
the task; it is my conviction that an interdisciplinary approach
using ever-improved analytical tools in concert with much
refined computational methods114 is the most promising way
forward.
I thank all coworkers and collaboration partners who
participated in the iron catalysis project for their invaluable
intellectual and experimental contributions; their names appear
in the references. Generous financial support by the Max-
Planck-Society and the Fonds der Chemischen Industrie is
gratefully acknowledged.
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