Bull - Chem.Soc - JPN., 2021, 94, 666-677 (Furstner Review Iron) PDF
Bull - Chem.Soc - JPN., 2021, 94, 666-677 (Furstner Review Iron) PDF
Bull - Chem.Soc - JPN., 2021, 94, 666-677 (Furstner Review Iron) PDF
Alois Fürstner
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).
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 reagents of choice.14 Many reactions proceed with excep-
iron catalysis. It was used in Kochi’s pioneering reports on tionally high rates at or (much) below room temperature.
reactions of certain Grignard reagents with alkenyl halides in Because of this favorable kinetic profile, various functional
the presence of simple iron salts;6 the first publications of this groups remain untouched, which one would expect to react
series pre-date the seminal discoveries of nickel- and palladium with Grignard reagents otherwise. Electron deficient aryl- or
cross coupling that triggered the avalanche shortly thereafter.7 heteroaryl chlorides are the most adequate substrates, whereas
Interestingly enough, scattered examples of what would nowa- triflates are typically required as the leaving group in case of
days certainly be called iron catalyzed “homo coupling” and electron-rich reaction partners. Unfortunately, the analogous
“cross coupling” had already been published prior to Kochi’s aryl-aryl coupling turned out to be of limited scope;14 since the
work, although the impact was arguably marginal.8 original report, however, much progress has been achieved in
The potential advantages notwithstanding, the scope of early this important field, even though a completely general proce-
iron catalyzed cross coupling was narrow. Largely variable dure is still awaited.24
outcomes were recorded even for alkenyl halides,6,9 and only For the many favorable attributes, iron catalyzed aryl/alkyl
few other types of electrophiles were found suitable.10 This cross coupling was rapidly embraced by the community and its
limitation was perhaps a major reason for a “latency period” scope was further extended: for example, many additional and
with little activity in the field, which lasted nearly until the turn rather “unconventional” leaving groups proved viable, which
of the millennium. Only at this point in time was the field traditional palladium catalysts fail to activate (aryl sulfamates,
thoroughly revisited: several independent reports showcased carbamates, carboxylates, phosphonates, (thio)ethers, trialkyl-
that the potential of iron catalysis for CC-bond formation in ammonium salts etc.).1823 Moreover, certain nucleophiles
general and cross coupling in particular had been largely other than Grignard reagents can be used, even though there
underestimated.1114 is room for further improvement.12,1823 Applications to natural
Our group’s first systematic foray pursued the simple but product synthesis corroborate the utility of this chemistry.25
important goal of extending iron catalyzed cross coupling to This notion is exemplified by the serial cross-coupling of the
aryl halides. Though arguably the most important type of elec- bifunctional pyridine derivative 3 with two different Grignard
trophiles, they had neither been addressed by Kochi nor anyone reagents in one pot (Scheme 2); the resulting product 5 was
else prior to our work. Gratifyingly, many aryl chlorides, then swiftly transformed into muscopyridine by a one-pot ring
-triflates and even -tosylates were found to react well with closing metathesis/hydrogenation cascade.26,27 Since iron
Grignard reagents in the presence of iron salts as simple as catalyzed cross coupling reactions scale well,28 several appli-
Fe(acac)3 (Scheme 1).14 External ligands can be used but are cations from industrial laboratories to various bioactive com-
not mandatory, whereas co-solvents or additives such as N- pounds have already been disclosed (Figure 1).29,30
methylpyrrolidone (NMP) or TMEDA usually prove advanta- In view of the foregoing, it may not come as a surprise
geous; they are believed to control the speciation in solution, that we found other electrophiles such as alkenyl triflates
even though their exact role is hardly understood at the molec- (tosylates) or acid chlorides to be well-behaved reaction part-
ular level.15 NMP was later classified as potentially reprotoxic, ners too;31 many additional types of substrates were added to
but many benign alternatives of similar efficacy were found the list by other research groups.1823 Once again, a growing
since.16 number of applications to natural product synthesis bears
Several lines of evidence prove that it is the iron that witness to the power of this chemistry. The straightforward
accounts for the cross coupling and not trace impurities in the synthesis of cubebene by a sequence of π-acid catalyzed
precatalyst (Cu, Pd etc.).17 Specifically: (i) iron salts of the cycloisomerization of an enyne with concomitant 1,2-acyl
highest available purity show unchanged performance; (ii) aryl shift32 followed by an iron catalyzed cross coupling is repre-
chlorides are typically much better substrates than the corre- sentative (Scheme 3).25,3336
sponding bromides or iodides,14 very much opposite to what is
observed with copper- or palladium catalysts; (iii) the reactions 3. Steps Beyond the Canon: Alkyl Electrophiles
proceed with unprecedented rates at temperatures as low as Where applicable, iron catalysis has notable merits for being
¹78 °C in some cases, at which copper or palladium catalysts fast, productive, mild, benign and cost-effective. From a con-
usually fail to activate aryl chlorides; (iv) structurally well- ceptual perspective, however, the transformations described in
defined and fully characterized iron complexes were found that
are even better (pre)catalysts than simple iron salts.
BrMg
Because several excellent reviews on this topic are available, Cl N 4
MgBr
a summary in “al fresco” style may suffice at this point.1823 In Cl N OTf Fe-salene (5 mol%)
80%
the original format, alkylmagnesium halides proved to be the 3 THF/NMP, 0°C 4
n-Hexyl-MgBr O N
O
N Muscopyridine
Fe(acac)3 (5 mol%) OMe
OMe
Scheme 1. Prototypical iron catalyzed aryl/alkyl coupling Scheme 2. Sequential “one-pot” cross coupling en route to
reaction. muscopyridine.
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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
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 The new entry into non-terminal alkynes has served natural
propargyl epoxide; application to the total synthesis of product synthesis well. Whereas the copper-catalyzed proce-
amphidinolide Y. dure furnished key building blocks for our recent total syn-
theses of tulearin A and C,61,62 kendomycin,65 and 5,6-
furnish allenol 27 in less than five minutes reaction time. The dihydrocineromycin B,66 the iron-catalyzed variant proved
fact that the syn-isomer was formed preferentially (dr = 8:1) is instrumental for our approaches to callyspongiolide67 and
thought to reflect a “directed delivery” of the nucleophile via brefeldin A (Scheme 8);68 all of these projects relied on ring
pre-coordination (A) of the (loaded) oxophilic iron catalyst to closing alkyne metathesis (RCAM) as an exquisite means to
the epoxide O-atom; for this stereochemical course, the reac- forge macrocyclic frameworks.69,70 The reactions were per-
tion is complementary to the anti-selective opening of propar- formed on multigram scale and show that chiral centers α to the
gyl epoxides with organocopper reagents. The axial chirality of former lactone carbonyl remain intact.
27 was then transmitted to the tertiary ether center upon acti-
vation of the allene with the aid of a carbophilic Lewis acid.56 5. Iron-Catalyzed Ring-Opening/Cross Coupling
The resulting product 28 served as key building block for the In recognition of the fact that different types of alkenyl elec-
total syntheses of amphidinolide X and Y.55,57,58 trophiles are amenable to iron catalyzed cross coupling, we
explored whether compounds comprising such a motif as part
4. Internal Alkynes Derived from Lactones of a heterocyclic ring react analogously. 2-Pyrones fall into this
Because of their activated carbonyl character, many lactones category, not least because they show little aromatic character
are amenable to Wittig-type olefination, which ordinary esters and can be viewed as cyclic enol ester derivatives.
do not undergo. This propensity can be used to access gem- In line with this notion, treatment of 32 with MeMgBr and
dichloro olefin derivatives such as 30.59 On treatment with catalytic amounts of Fe(acac)3 in toluene or Et2O at low temper-
lithium sand, these compounds afford the corresponding ature furnished acid 33 in good yield and excellent selectivity
terminal alkynes.60 We saw an opportunity to extend the scope (Scheme 9).71 For its “non-thermodynamic” Z,E-configuration,
and reach internal alkynes simply upon replacement of lithium the product is highly isomerization-prone; actually, it sufficed
by organolithium reagents RLi.61 to warm the mixture to ambient temperature prior to work-up
The desired reaction takes place even in the absence of a to transform the kinetic product into the more stable E,E-
catalyst, but it is much accelerated by either copper or iron isomer.71 To the best of our knowledge, this kind of formal “ring
salts; in the latter case, a mixture of Fe(acac)3 and 1,2- opening/cross coupling” of pyrones has no precedent in palla-
diaminobenzene proved optimal.62 This variant works partic- dium catalysis; it is enabling in that it provides access to
ularly well for exo-dichloroolefins derived from five-membered highly substituted di-unsaturated acid derivatives that are
lactones (Scheme 8). The catalyst likely promotes the initial difficult to make otherwise.
metal/halogen exchange with formation of a metal vinylidene; From the conceptual viewpoint, this transformation marks a
intermediates of type B are known to be electrophilic63 and new frontier for cross coupling in general, because the former
capable of intercepting a second equivalent of RLi to give C “leaving group” is retained as an integral part of the result-
prior to reductive elimination.62 Note that the substituent R ing product. Moreover, it shows that heterocycles may be an
attached to the triple bond is derived from the nucleophile, underutilized pool of substrates that deserves more attention.
which distinguishes this transformation from a classical Corey- Because of the exceptionally mild conditions, it was hoped
Fuchs alkynylation/alkylation sequence.64 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 OPMB
N N
OTBDPS OTBDPS (CO)3Fe
MeMgBr HOOC Ph
BocHN Fe(acac)3 (30 mol%) BocHN O O O O
73% (97% brsm) 37
O O 22
O O O O Me
34 35
S S
OPMB NMe 2
N N
O O
O O
BocHN H2N
Pateamin A
O O
O 36 O
670 | Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319 © 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
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
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[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
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 and only three organic residues in the first coordination
C-bonds can be cleaved by this catalytic process: in the case of sphere.44,98
product 53, two new CC bonds were formed while one CC More recent studies using advanced spectroscopies to study
bond was concomitantly broken during this unorthodox cyclo- freeze-trapped intermediates generated in situ confirmed the
isomerization process.96 intervention of ate-complexes in several iron catalyzed CC-
It is appropriate to mention here that palladium catalysts bond forming processes. Moreover, it has been convincingly
can serve similar purposes. Actually, they allow aryl groups to shown that ate-complexes are subject to facile ligand exchange
be transferred, which the iron-based system does not do well. and evolve with time to lower oxidation states.99 They can
What is remarkable though is the fact that iron catalysis undergo either two-electron reduction with formation of Fe(0)
proceeds rapidly at ¹30 °C, whereas the palladium catalyzed or single-electron reduction with formation of Fe(+1). Strik-
reactions mandate heating to +90 °C.96 This differential illus- ingly, the latter process is neither the result of homolytic cleav-
trates the exceptional driving force pooled in the iron catalyst, age or disproportionation, as one might tend to think, but rather
which might well be harnessed in other settings too. a consequence of the transient formation of dinuclear entities,
which must be accessible on steric ground for the reaction to
9. Vignette: Iron Ate-Complexes proceed. This insight illustrates the intricacy of this chemistry
Early observations suggested that reactions of iron salts with and arguably provides guidance for future catalyst design.99,100
higher alkyl-Grignard reagents lead to the formation of low- A particular highlight is the study into the ferrate species
valent iron complexes by β-hydride elimination reactions formed on treatment of FeX3 with excess RMgBr (R = Me, Et).
and/or reductive coupling processes (compare complex 48, In the absence of NMP, ferrate cluster species of the formal
Scheme 15).14,31 In contrast, nucleophiles that cannot undergo composition [R12Fe8][MgCl(thf )] are generated;101,102 in the
either reduction mechanism were supposed to furnish iron-ate presence of NMP, in contrast, [R3Fe][Mg(nmp)6] is formed
complexes in analogy to the well-known cuprates invoked in in situ (even in case of R = Et, where β-hydide elimination is
much of organocopper chemistry.14,31 expected to take place).15,103 These latter complexes almost
The first such ferrate species that was shown to be relevant in certainly represent the reactive intermediates accountable for
the context of iron cross coupling was a “super-ate” complex the seminal results described by Kochi and coworkers on the
formed on reaction of FeCl2 with excess MeLi.97 The resulting iron catalyzed cross coupling of alkenyl halides.6 One must
homoleptic species [(Me4Fe)(MeLi)][Li¢(OEt2)]2 (54) carries appreciate the difficulty in characterizing reactive complexes of
four methyl groups in a tetrahedral arrangement about the this level of complexity, which are extremely air- and moisture
Fe(+2) center (Figure 3); three of them entertain additional sensitive, and, in case of [R12Fe8][MgCl(thf )], also paramag-
contacts to three escorting lithium counterions, which form a netic. This formidable “analytical frontier”4 is a major hurdle
tetrahedral metal framework with the iron center. Strikingly and the progress in the understanding of iron catalysis achieved
though, the cluster incorporates a fifth methyl group (C5) in recent year therefore all the more impressive.
devoid of any direct interaction with the iron atom.90,97 This
unusual complex proved competent, inter alia, for the alkyla- 10. A Case Study in CH Activation
tion of alkenyl halides, alkenyl triflates, and acid chlorides, as Base metal catalysts in general and iron catalysts in par-
well as for pyrone ring opening/cross coupling.71,90 PhLi ticular show great promise in CH activation reactions.104106
afforded the related ate-complex [Ph4Fe][Li¢(OEt2)2][Li¢(1,4- As this topic is beyond the scope of the present Account, a
dioxane)], even though it lacks a fifth RLi entity.90 In con- single case study must suffice to illustrate the point. Specif-
trast, more bulky aryl-Grignard reagents give “ordinary” ate- ically, ligand exchange between the Fe(0) ethylene complex 48
complexes of type [Ar3Fe]¹ carrying a single negative charge 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
Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319 © 2021 The Chemical Society of Japan | 673
entails CC bond formation and regenerates a low-valent iron inorganic Chemistry - Inorganic Elements in the Chemistry of Life:
center poised for the next CH activation event that forms the An Introduction and Guide, 2nd Ed., Wiley, 2013.
final product 55.89,94 The endo-orientation of the ethyl sub- 2 R. M. Bullock, ed., Catalysis without Precious Metals.
stituent in 55, which was ascertained by X-ray diffraction, Wiley-VCH: Weinheim, 2010.
supports this involved mechanistic scenario. 3 Polymer synthesis is arguably the most important excep-
The elementary steps underlying the cascade comprised of tion.
two consecutive CH activation events and an interwoven 4 A. Fürstner, ACS Cent. Sci. 2016, 2, 778.
5 R. M. Bullock, J. G. Chen, L. Galiardi, P. J. Chirik, O. K.
stereoselective CC-bond forming step are deemed enabling:
Farha, C. H. Hendon, C. W. Jones, J. A. Keith, J. Klosin, S. D.
the overall reaction can also be seen as the prototype of an
Minteer, R. H. Morris, A. T. Radosevich, T. B. Rauchfuss, N. A.
unconventional “cross coupling” process employing cheap
Strotman, A. Vojvodic, T. R. Ward, J. Y. Yang, V. Surendranath,
ethylene as pre-nucleophile in lieu of a preformed organo-
Science 2020, 369, 786.
metallic reagent. 6 a) M. Tamura, J. K. Kochi, J. Am. Chem. Soc. 1971, 93,
11. Conclusion 1487. b) S. M. Neumann, J. K. Kochi, J. Org. Chem. 1975, 40,
599. c) R. S. Smith, J. K. Kochi, J. Org. Chem. 1976, 41, 502.
This personal Account article does not provide a compre- d) J. K. Kochi, Acc. Chem. Res. 1974, 7, 351.
hensive treatise of iron catalyzed CC bond formation. Rather 7 For a historical perspective, see: C. C. C. Johansson
it is meant to showcase that the use of this base metal (and its Seechurn, M. O. Kitching, T. J. Colacot, V. Snieckus, Angew.
neighbors from the fourth period) provides valuable oppor- Chem., Int. Ed. 2012, 51, 5062.
tunities in “conventional” cross coupling; at the same time, it 8 a) M. S. Kharasch, E. K. Fields, J. Am. Chem. Soc. 1941,
opens intriguing perspectives for the discovery of genuinely 63, 2316. b) M. S. Kharasch, R. Morrison, W. H. Urry, J. Am.
novel transformations. Chem. Soc. 1944, 66, 368. c) M. S. Kharasch, F. L. Lambert, W. H.
The awareness that sustained catalysis mandates the devel- Urry, J. Org. Chem. 1945, 10, 298. d) G. Vavon, C. Chaminade, G.
opment of systems operating with base metals in general and Quesnel, C. R. Hebd. Seances Acad. Sci. 1945, 220, 850. e) W. C.
iron in particular is rapidly increasing. Yet, the understanding Percival, R. B. Wagner, N. C. Cook, J. Am. Chem. Soc. 1953, 75,
of many of their fundamental properties lags behind: What are 3731.
the best ways to characterize fleeting paramagnetic intermedi- 9 G. A. Molander, B. J. Rahn, D. C. Shubert, S. E. Bonde,
ates?41,107 Where and how does the spin-state come into play Tetrahedron Lett. 1983, 24, 5449.
10 a) T. Mukaiyama, T. Takeda, M. Osaki, Chem. Lett. 1977,
and where does spin crossover intervene (“two-state reactiv-
1165. b) J. L. Fabre, M. Julia, J.-N. Verpeaux, Tetrahedron Lett.
ity”)?108110 How can ligands be designed that allow the spin-
1982, 23, 2469. c) C. Cardellicchio, V. Fiandanese, G. Marchese,
state to be controlled? Will a given complex favor single-
L. Ronzini, Tetrahedron Lett. 1985, 26, 3595. d) A. Yanagisawa,
electron or two-electron transfer?111 In which cases is dispro- N. Nomura, H. Yamamoto, Tetrahedron 1994, 50, 6017.
portionation a shortcut for “regular” redox events? How can 11 a) G. Cahiez, H. Avedissian, Synthesis 1998, 1199. b) G.
“non-innocent” ligands and/or other metal/ligand cooperativ- Cahiez, S. Marquais, Pure Appl. Chem. 1996, 68, 53.
ity be used to advantage?112,113 12 The first example from our laboratory is contained in a
Certain answers to these and related questions can be found study on organomanganese reagents, see: A. Fürstner, H. Brunner,
in the pertinent literature, but a fully comprehensive picture Tetrahedron Lett. 1996, 37, 7009.
does not emerge from the current state-of-the-art; some of the 13 a) M. Nakamura, A. Hirai, E. Nakamura, J. Am. Chem. Soc.
examples discussed above corroborate this notion. Although 2000, 122, 978. b) M. Nakamura, K. Matsuo, T. Inoue, E.
the challenges in this field of research are tremendous, the Nakamura, Org. Lett. 2003, 5, 1373.
ingenuity of the next generation of scientists is certainly up to 14 a) A. Fürstner, A. Leitner, M. Méndez, H. Krause, J. Am.
the task; it is my conviction that an interdisciplinary approach Chem. Soc. 2002, 124, 13856. b) A. Fürstner, A. Leitner, Angew.
using ever-improved analytical tools in concert with much Chem., Int. Ed. 2002, 41, 609.
refined computational methods114 is the most promising way 15 For an important exception, see: S. B. Munoz, S. L.
forward. Daifuku, J. D. Sears, T. M. Baker, S. H. Carpenter, W. W.
Brennessel, M. L. Neidig, Angew. Chem., Int. Ed. 2018, 57, 6496.
I thank all coworkers and collaboration partners who 16 a) E. Bisz, M. Kardela, M. Szostak, ChemCatChem 2019,
participated in the iron catalysis project for their invaluable 11, 5733. b) E. Bisz, M. Szostak, J. Org. Chem. 2019, 84, 1640.
c) G. Cahiez, G. Lefèvre, A. Moyeux, O. Guerret, E. Gayon, L.
intellectual and experimental contributions; their names appear
Guillonneau, N. Lefevre, Q. Gu, E. Zhou, Org. Lett. 2019, 21,
in the references. Generous financial support by the Max-
2679.
Planck-Society and the Fonds der Chemischen Industrie is
17 Putative iron catalyzed CN, CO, and CS coupling
gratefully acknowledged. reactions were later shown to be caused by copper impurities in the
chosen iron salts, see: S. L. Buchwald, C. Bolm, Angew. Chem.,
References Int. Ed. 2009, 48, 5586.
# Dedicated to Prof. Eiichi Nakamura on the occasion of his 18 E. Nakamura, T. Hatakeyama, S. Ito, K. Ishizuka, L. Ilies,
70th birthday and in recognition of his seminal contributions to M. Nakamura, Org. React. 2014, 83, 1.
science, including pioneering work on iron catalysis. 19 I. Bauer, H.-J. Knölker, Chem. Rev. 2015, 115, 3170.
1 a) I. Bertini, H. B. Gray, S. J. Lippard, J. S. Valentine, ed., 20 A. Fürstner, Org. Synth. 2019, 96, 1.
Bioinorganic Chemistry, University Science Books: Mill Valley, 21 a) B. D. Sherry, A. Fürstner, Acc. Chem. Res. 2008, 41,
CA, 1994. b) W. Kaim, B. Schwederski, A. Klein, ed., Bio- 1500. b) A. Fürstner, Angew. Chem., Int. Ed. 2009, 48, 1364. c) A.
674 | Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319 © 2021 The Chemical Society of Japan
Fürstner, R. Martin, Chem. Lett. 2005, 34, 624. 35 A. Hamajima, M. Isobe, Org. Lett. 2006, 8, 1205.
22 a) A. Piontek, E. Bisz, M. Szostak, Angew. Chem., Int. 36 Q. Liu, Y. Deng, A. B. Smith, J. Am. Chem. Soc. 2017, 139,
Ed. 2018, 57, 11116. b) D. Lübken, M. Saxarra, M. Kalesse, 13668.
Synthesis 2019, 51, 161. c) G. Cahiez, A. Moyeaux, J. Cossy, 37 R. Martin, A. Fürstner, Angew. Chem., Int. Ed. 2004, 43,
Adv. Synth. Catal. 2015, 357, 1983. d) O. M. Kuzmina, A. K. 3955.
Steib, A. Moyeux, G. Cahiez, P. Knochel, Synthesis 2015, 47, 38 M. Nakamura, K. Matsuo, S. Ito, E. Nakamura, J. Am.
1696. e) T. L. Mako, J. A. Byers, Inorg. Chem. Front. 2016, 3, Chem. Soc. 2004, 126, 3686.
766. f ) T. Mesganaw, N. K. Garg, Org. Process Res. Dev. 2013, 39 T. Nagano, T. Hayashi, Org. Lett. 2004, 6, 1297.
17, 29. g) W. M. Czaplik, M. Mayer, J. Cvengroš, A. 40 See the following for leading references and literature cited
Jacobi von Wangelin, ChemSusChem 2009, 2, 396. h) E. B. therein: a) R. B. Bedford, D. W. Bruce, R. M. Frost, M. Hird,
Bauer, Curr. Org. Chem. 2008, 12, 1341. Chem. Commun. 2005, 4161. b) G. Cahiez, V. Habiak, C. Duplais,
23 a) B. Plietker, ed., Iron Catalysis. Fundamentals and A. Moyeux, Angew. Chem., Int. Ed. 2007, 46, 4364. c) T.
Applications, Springer: Heidelberg, 2011; Top. Organomet. Chem., Hatakeyama, S. Hashimoto, K. Ishizuka, M. Nakamura, J. Am.
Vol. 33. b) E. B. Bauer, ed., Iron Catalysis II; Ed.; Springer Chem. Soc. 2009, 131, 11949. d) R. B. Bedford, M. Betham, D. W.
International Publishing: Cham, CH, 2015; Top. Organomet. Bruce, A. A. Danopoulos, R. M. Frost, M. Hird, J. Org. Chem.
Chem., Vol. 50. 2006, 71, 1104. e) R. R. Chowdhury, A. K. Crane, C. Fowler, P.
24 For leading references, see the following and literature Kwong, C. M. Kozak, Chem. Commun. 2008, 94. f ) A. Guérinot,
cited therein: a) T. Hatakeyama, S. Hashimoto, K. Ishizuka, M. S. Reymond, J. Cossy, Angew. Chem., Int. Ed. 2007, 46, 6521.
Nakamura, J. Am. Chem. Soc. 2009, 131, 11949. b) I. Sapounzis, g) G. Bauer, M. D. Wodrich, R. Scopelliti, X. Hu, Organometallics
W. Lin, C. C. Kofink, C. Despotopoulou, P. Knochel, Angew. 2015, 34, 289. h) L. Adak, S. Kawamura, G. Toma, T. Takenaka,
Chem., Int. Ed. 2004, 43, 1454. c) L. Wang, Y.-M. Wei, Y. Zhao, K. Isozaki, H. Takaya, A. Orita, H. C. Li, T. K. M. Shing, M.
X.-F. Duan, J. Org. Chem. 2019, 84, 5176. Nakamura, J. Am. Chem. Soc. 2017, 139, 10693.
25 a) J. Legros, B. Figadère, Nat. Prod. Rep. 2015, 32, 1541. 41 a) R. Agata, H. Takaya, H. Matsuda, N. Nakatani, K.
b) J. E. Zweig, D. E. Kim, T. R. Newhouse, Chem. Rev. 2017, 117, Takeuchi, T. Iwamoto, T. Hakateyama, M. Nakamura, Bull. Chem.
11680. c) P. DaBell, S. P. Thomas, Synthesis 2020, 52, 949. Soc. Jpn. 2019, 92, 381. b) J. D. Sears, P. G. N. Neate, M. L.
26 A. Fürstner, A. Leitner, Angew. Chem., Int. Ed. 2003, 42, Neidig, J. Am. Chem. Soc. 2018, 140, 11872. c) T. Parchomyk, K.
308. Koszinowski, Synthesis 2017, 49, 3269.
27 For other early applications from this laboratory, see: a) B. 42 M. Jin, L. Adak, M. Nakamura, J. Am. Chem. Soc. 2015,
Scheiper, F. Glorius, A. Leitner, A. Fürstner, Proc. Natl. Acad. Sci. 137, 7128.
U.S.A. 2004, 101, 11960. b) A. Fürstner, D. De Souza, L. Parra- 43 C. Gregg, C. Gunawan, A. W. Y. Ng, S. Wimala, S.
Rapado, J. Jensen, Angew. Chem., Int. Ed. 2003, 42, 5358. c) G. Wickremasinghe, M. A. Rizzacasa, Org. Lett. 2013, 15, 516.
Seidel, D. Laurich, A. Fürstner, J. Org. Chem. 2004, 69, 3950. 44 C.-L. Sun, H. Krause, A. Fürstner, Adv. Synth. Catal. 2014,
d) A. Fürstner, D. De Souza, L. Turet, M. D. B. Fenster, L. Parra- 356, 1281.
Rapado, C. Wirtz, R. Mynott, C. W. Lehmann, Chem.®Eur. J. 45 For a different diphosphine ligand that enables similar
2007, 13, 115. e) A. Fürstner, D. Kirk, M. D. B. Fenster, C. Aissa, transformations, see: T. Hatakeyama, Y. Fujiwara, Y. Okada, T.
D. De Souza, C. Nevado, T. Tuttle, W. Thiel, O. Müller, Chem.® Itoh, T. Hashimoto, S. Kawamura, K. Ogata, H. Takaya, M.
Eur. J. 2007, 13, 135. Nakamura, Chem. Lett. 2011, 40, 1030.
28 A. Fürstner, A. Leitner, G. Seidel, Org. Synth. 2004, 81, 33. 46 a) P. A. Wender, S. K. Singh, Tetrahedron Lett. 1990, 31,
29 a) N. Tewari, N. Maheshwari, R. Medhane, H. Nizar, M. 2517. b) P. A. Wender, S. K. Singh, Tetrahedron Lett. 1985, 26,
Prasad, Org. Process Res. Dev. 2012, 16, 1566. b) P. J. Rushworth, 5987.
D. G. Hulcoop, D. J. Fox, J. Org. Chem. 2013, 78, 9517. c) C. 47 D. J. Tindall, H. Krause, A. Fürstner, Adv. Synth. Catal.
Risatti, K. J. Natalie, Jr., Z. Shi, D. A. Conlon, Org. Process Res. 2016, 358, 2398.
Dev. 2013, 17, 257. d) F. Bartoccini, G. Piersanti, S. Armaroli, A. 48 C. L. Hugelshofer, V. Palani, R. Sarpong, J. Org. Chem.
Cerri, W. Cabri, Tetrahedron Lett. 2014, 55, 1376. e) S. M. 2019, 84, 14069.
Andersen, M. Bollmark, R. Berg, C. Fredriksson, S. Karlsson, C. 49 For a very recent report on the cross coupling of a tert-
Liljeholm, H. Sörensen, Org. Process Res. Dev. 2014, 18, 952. iodide with a bicyclo[1.1.1]pentane backbone, see: J. Nugent,
f ) S. Gangula, U. K. Neelam, S. R. Baddam, V. H. Dahanukar, R. B. R. Shire, D. F. J. Caputo, H. D. Pickford, F. Nightingale, I. T. T.
Bandichhor, Org. Process Res. Dev. 2015, 19, 470. g) P. Mullens, Houlsby, J. J. Mousseau, E. A. Anderson, Angew. Chem., Int. Ed.
E. Cleator, M. McLaughlin, B. Bishop, J. Edwards, A. Goodyear, 2020, 59, 11866.
T. Andreani, Y. Jin, J. Kong, H. Li, M. Williams, M. Zacuto, Org. 50 D. J. Pasto, S.-K. Chou, A. Waterhouse, R. H. Shults, G. F.
Process Res. Dev. 2016, 20, 1075. h) G. Cahiez, O. Guerret, A. Hennion, J. Org. Chem. 1978, 43, 1385.
Moyeux, S. Dufour, N. Lefèvre, Org. Process Res. Dev. 2017, 21, 51 A. Fürstner, M. Méndez, Angew. Chem., Int. Ed. 2003, 42,
1542. i) P. Chourreu, O. Guerret, L. Guillonneau, E. Gayon, G. 5355.
Lefèvre, Org. Process Res. Dev. 2020, 24, 1335. 52 B. D. Sherry, A. Fürstner, Chem. Commun. 2009, 7116.
30 For iron-catalyzed coupling in flow, see: Y. Deng, X.-J. 53 a) S. N. Kessler, J.-E. Bäckvall, Angew. Chem., Int. Ed.
Wei, X. Wang, Y. Sun, T. Noel, Chem.®Eur. J. 2019, 25, 14532. 2016, 55, 3734. b) S. N. Kessler, F. Hundemer, J. E. Bäckvall, ACS
31 B. Scheiper, M. Bonnekessel, H. Krause, A. Fürstner, Catal. 2016, 6, 7448.
J. Org. Chem. 2004, 69, 3943. 54 For an exception, see: I. Manjon-Mata, M. T. Quiros, E.
32 V. Mamane, T. Gress, H. Krause, A. Fürstner, J. Am. Chem. Bunuel, D. J. Cardenas, Adv. Synth. Catal. 2020, 362, 146.
Soc. 2004, 126, 8654. 55 O. Lepage, E. Kattnig, A. Fürstner, J. Am. Chem. Soc.
33 A. Fürstner, P. Hannen, Chem.®Eur. J. 2006, 12, 3006. 2004, 126, 15970.
34 A. Fürstner, A. Schlecker, Chem.®Eur. J. 2008, 14, 9181. 56 a) A. Fürstner, P. W. Davies, Angew. Chem., Int. Ed. 2007,
Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319 © 2021 The Chemical Society of Japan | 675
46, 3410. b) A. Fürstner, Acc. Chem. Res. 2014, 47, 925. d) J. M. Takacs, P. W. Newsome, C. Kuehn, F. Takusagawa,
57 A. Fürstner, E. Kattnig, O. Lepage, J. Am. Chem. Soc. Tetrahedron 1990, 46, 5507.
2006, 128, 9184. 84 P. A. Wender, M. P. Croatt, N. M. Deschamps, in
58 See also: T. Kang, S. B. Song, W.-Y. Kim, B. G. Kim, H.-Y. Comprehensive Organometallic Chemistry III, (I. Ojima, Ed.),
Lee, J. Am. Chem. Soc. 2014, 136, 10274. Elsevier, 2007, Vol. 10, pp. 603648.
59 a) M. Suda, A. Fukushima, Tetrahedron Lett. 1981, 22, 759. 85 K. Jonas, L. Schieferstein, C. Krüger, Y.-H. Tsay, Angew.
b) M. Lakhrissi, Y. Chapleur, J. Org. Chem. 1994, 59, 5752. Chem., Int. Ed. Engl. 1979, 18, 550.
60 J. S. Yadav, V. Prahlad, M. C. Chander, J. Chem. Soc., 86 A. Fürstner, K. Majima, R. Martin, H. Krause, E. Kattnig,
Chem. Commun. 1993, 137. R. Goddard, C. W. Lehmann, J. Am. Chem. Soc. 2008, 130, 1992.
61 K. Lehr, R. Mariz, L. Leseurre, B. Gabor, A. Fürstner, 87 A. Fürstner, R. Martin, K. Majima, J. Am. Chem. Soc. 2005,
Angew. Chem., Int. Ed. 2011, 50, 11373. 127, 12236.
62 K. Lehr, S. Schulthoff, Y. Ueda, R. Mariz, L. Leseurre, B. 88 For a leading review on an alternative ligand design that
Gabor, A. Fürstner, Chem.®Eur. J. 2015, 21, 219. enables yet other valuable iron catalyzed cycloaddition reactions,
63 a) M. Topolski, M. Duraisamy, J. Rachon, J. Gawronski, K. see: P. J. Chirik, Angew. Chem., Int. Ed. 2017, 56, 5170.
Gawronska, V. Goedken, H. M. Walborsky, J. Org. Chem. 1993, 89 A. Casitas, H. Krause, S. Lutz, R. Goddard, E. Bill, A.
58, 546. b) H. Yanagisawa, K. Miura, M. Kitamura, K. Narasaka, Fürstner, Organometallics 2018, 37, 729.
K. Ando, Bull. Chem. Soc. Jpn. 2003, 76, 2009. 90 A. Fürstner, R. Martin, H. Krause, G. Seidel, R. Goddard,
64 E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769. C. W. Lehmann, J. Am. Chem. Soc. 2008, 130, 8773.
65 L. Hoffmeister, P. Persich, A. Fürstner, Chem.®Eur. J. 91 J. P. Collman, Acc. Chem. Res. 1975, 8, 342.
2014, 20, 4396. 92 B. Bogdanovic, M. Schwickardi, Angew. Chem., Int. Ed.
66 S. M. Rummelt, J. Preindl, H. Sommer, A. Fürstner, Angew. 2000, 39, 4610.
Chem., Int. Ed. 2015, 54, 6241. 93 M. L. Neidig, S. H. Carpenter, D. J. Curran, J. C. DeMuth,
67 a) G. Mata, B. Wölfl, A. Fürstner, Chem.®Eur. J. 2019, 25, V. E. Fleichauer, T. E. Iannuzzi, P. G. N. Neate, J. D. Sears, N. J.
246. b) B. Wölfl, G. Mata, A. Fürstner, Chem.®Eur. J. 2019, 25, Wolford, Acc. Chem. Res. 2019, 52, 140.
255. 94 A. Casitas, H. Krause, R. Goddard, A. Fürstner, Angew.
68 M. Fuchs, A. Fürstner, Angew. Chem., Int. Ed. 2015, 54, Chem., Int. Ed. 2015, 54, 1521.
3978. 95 A. Casitas, J. A. Rees, R. Goddard, E. Bill, S. DeBeer, A.
69 A. Fürstner, Angew. Chem., Int. Ed. 2013, 52, 2794. Fürstner, Angew. Chem., Int. Ed. 2017, 56, 10108.
70 A. Fürstner, Science 2013, 341, 1229713. 96 a) P.-G. Echeverria, A. Fürstner, Angew. Chem., Int. Ed.
71 C.-L. Sun, A. Fürstner, Angew. Chem., Int. Ed. 2013, 52, 2016, 55, 11188. b) F. Gomes, P.-G. Echeverria, A. Fürstner,
13071. Chem.®Eur. J. 2018, 24, 16814.
72 P. T. Northcote, J. W. Blunt, M. H. G. Munro, Tetrahedron 97 A. Fürstner, H. Krause, C. W. Lehmann, Angew. Chem., Int.
Lett. 1991, 32, 6411. Ed. 2006, 45, 440.
73 D. Romo, N. S. Choi, S. Li, I. Buchler, Z. Shi, J. O. Liu, 98 R. B. Bedford, P. B. Brenner, E. Carter, P. M. Cogswell,
J. Am. Chem. Soc. 2004, 126, 10582. M. F. Haddow, J. N. Harvey, D. M. Murphy, J. Nunn, C. H.
74 L. Shen, J. Pelletier, Nat. Prod. Rep. 2020, 37, 609. Wondall, Angew. Chem., Int. Ed. 2014, 53, 1804.
75 A. Fürstner, Angew. Chem., Int. Ed. 2018, 57, 4215. 99 a) L. Rousseau, C. Herrero, M. Clémancey, A. Imberdis, G.
76 a) W. Chaladaj, M. Corbet, A. Fürstner, Angew. Chem., Int. Blondin, G. Lefèvre, Chem.®Eur. J. 2020, 26, 2417. b) M.
Ed. 2012, 51, 6929. b) J. Preindl, K. Jouvin, D. Laurich, G. Seidel, Clémancey, T. Cantat, G. Blondin, J.-M. Latour, P. Dorlet, G.
A. Fürstner, Chem.®Eur. J. 2016, 22, 237. c) J. Preindl, S. Lefèvre, Inorg. Chem. 2017, 56, 3834.
Schulthoff, C. Wirtz, J. Lingnau, A. Fürstner, Angew. Chem., Int. 100 See also: a) T. Parchomyk, K. Koszinowski, Chem.®Eur. J.
Ed. 2017, 56, 7525. 2018, 24, 16342. b) T. Parchomyk, S. Demeshko, F. Meyer, K.
77 C.-X. Zhuo, A. Fürstner, J. Am. Chem. Soc. 2018, 140, Koszinowski, J. Am. Chem. Soc. 2018, 140, 9709.
10514. 101 S. B. Munoz, S. L. Daifuku, W. W. Brennessel, M. L.
78 C.-X. Zhuo, A. Fürstner, Angew. Chem., Int. Ed. 2016, 55, Neidig, J. Am. Chem. Soc. 2016, 138, 7492.
6051. 102 T. Parchomyk, K. Koszinowski, Chem.®Eur. J. 2017, 23,
79 a) K. Fukuhara, H. Urabe, Tetrahedron Lett. 2005, 46, 603. 3213.
b) S. Okada, K. Arayama, R. Murayama, T. Ishizuka, K. Hara, N. 103 J. D. Sears, S. B. Munoz, S. L. Daifuku, A. A. Shaps, S. H.
Hirone, T. Hata, H. Urabe, Angew. Chem., Int. Ed. 2008, 47, 6860. Carpenter, W. W. Brennessel, M. L. Neidig, Angew. Chem., Int. Ed.
c) G. Sugano, K. Kawada, M. Shigeta, T. Hata, H. Urabe, 2019, 58, 2769.
Tetrahedron Lett. 2019, 60, 885. 104 a) E. Nakamura, N. Yoshikai, J. Org. Chem. 2010, 75,
80 L. Huang, Y. Gu, A. Fürstner, Chem.®Asian J. 2019, 14, 6061. b) N. Yoshikai, Isr. J. Chem. 2017, 57, 1117.
4017. 105 M. C. White, Science 2012, 335, 807.
81 H. Kurosawa, A. Yamamoto, ed., Fundamentals of Molec- 106 a) P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz, L.
ular Catalysis, Elsevier, 2003. Ackermann, Chem. Rev. 2019, 119, 2192. b) C.-L. Sun, B.-J. Li,
82 M. F. Semmelhack, in Organometallics in Synthesis. A Z. J. Shi, Chem. Rev. 2011, 111, 1293.
Manual (M. Schlosser, Ed.), 2nd Ed.; Wiley: Chichester, 2002; 107 S. H. Carpenter, N. L. Neidig, Isr. J. Chem. 2017, 57, 1106.
pp. 1003. 108 a) P. L. Holland, Acc. Chem. Res. 2015, 48, 1696. b) P. L.
83 a) J. P. Genet, J. Ficini, Tetrahedron Lett. 1979, 20, 1499. Holland, Acc. Chem. Res. 2008, 41, 905.
b) H. tom Dieck, R. Diercks, Angew. Chem., Int. Ed. Engl. 1983, 109 H. Nagashima, Bull. Chem. Soc. Jpn. 2017, 90, 761.
22, 778. c) K.-U. Baldenius, H. tom Dieck, W. A. König, D. 110 For an instructive case in cycloaddition chemistry, see: L.
Icheln, T. Runge, Angew. Chem., Int. Ed. Engl. 1992, 31, 305. Hu, H. Chen, J. Am. Chem. Soc. 2017, 139, 15564.
676 | Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319 © 2021 The Chemical Society of Japan
111 R. R. Arevalo, P. J. Chirik, J. Am. Chem. Soc. 2019, 141, 113 P. J. Chirik, K. Wieghardt, Science 2010, 327, 794.
9106. 114 F. Neese, Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012,
112 A. Quintard, J. Rodriquez, Angew. Chem., Int. Ed. 2014, 2, 73.
53, 4044.
Bull. Chem. Soc. Jpn. 2021, 94, 666–677 | doi:10.1246/bcsj.20200319 © 2021 The Chemical Society of Japan | 677