Discussion

Addendum for:
4-Nonylbenzoic Acid
Alois Fürstner1*
Max-Planck-Institut für Kohlenforschung

Original Article: Fürstner, A.; Leitner, A.; Seidel, G. Org. Synth. 2005, 81, 33–41.

A. O
O
nonylmagnesium bromide OMe
OMe Fe(acac)3 cat
Cl THF, 7 min, 0 °C to r.t.

O O
B.
OMe NaOH OH

H2O/MeOH

Largely driven by the needs of the life sciences and material chemistry,
the demand for ever more efficient procedures for cross coupling does not
seem to cease. While palladium-based methods continue to dominate the
field at large, the last decade has witnessed the development of a number of
innovative new concepts that enrich the portfolio of the practitioner and
even challenge organopalladium catalysis in certain ways.
One of these developments relates to the use of early transition metals
in lieu of palladium (or other noble metals); actually, this megatrend
reaches far beyond cross coupling chemistry.2 Utilitarian arguments render
iron a particularly attractive candidate, because it is cheap, abundant,
readily available, environmentally benign and hardly toxic for humans.
Moreover, research into homogeneous organoiron catalysis holds the
promise of opening entirely new fields of application by leveraging the
unique chemical properties of this element in the midst of the periodic
table.2,3

Org. Synth. 2019, 96, 1-15 1 Published on the Web 1/15/2019

DOI: 10.15227/orgsyn.096.0001 Ó 2019 Organic Syntheses, Inc.
 Scattered reports on the use of iron catalysts for “cross coupling” date
back to the time before this expression had actually been coined. The first
deliberate investigation was reported by Kochi and coworkers,4,5 who
showed that simple iron salts are capable of catalyzing the coupling of
Grignard reagents with alkenyl halides. Since the yields were variable and
the reaction seemed to lack generality, only few applications followed up on
this lead finding. It was Cahiez and coworkers who found that the
robustness of this process can be largely improved by using aprotic dipolar
cosolvents, preferentially N-methylpyrrolidin-2-one (NMP), which seems to
stabilize the actual catalyst and/or activates transiently formed organoiron
intermediates.6,7

Canonical Cross Coupling

Our group showed that the substrate scope reaches far beyond alkenyl
halides. In 2002, we reported the first iron-catalyzed cross coupling
reactions of aryl- and heteroaryl halides and -sulfonates (Figure 1).8-12
Shortly thereafter, alkenyl triflates (Figure 2) and acyl chlorides were found
to be equally privileged coupling partners.13 The 2005 Organic Syntheses
procedures describing the preparation of 4-nonylbenzoic acid, a component
of liquid crystalline materials, captures this state of development of iron
catalysis well in that it highlights the following notable virtues: (i) high
yields with Grignard reagents bearing ß-hydrogen atoms, (ii) exceptionally
fast reaction rates at (or below) room temperature, (iii) ready scalability, (iv)
convenient ligand-free conditions, and (v) a surprisingly large tolerance vis-
à-vis a number of functional groups that are susceptible to uncatalyzed
attack by Grignard reagents. Equally important is the fact that electron
deficient (hetero)aryl chlorides proved to be more suitable for iron-
catalyzed cross coupling than the corresponding bromides or iodides. When
working with electron rich (hetero)arenes, however, the corresponding
triflates have to be used.8,9,11 Moreover, it is possible to engage substrates
carrying more than one chloride or –sulfonate group either into exhaustive,
or site-selective or consecutive one-pot coupling reactions.9-13

Org. Synth. 2019, 96, 1-15 2 DOI: 10.15227/orgsyn.096.0001

 Figure 1. Iron-catalyzed alkyl/(hetero)aryl cross coupling reactions;9
(throughout this article, the segment derived from the Grignard reagent is
shown in red)

Figure 2. Iron-catalyzed cross coupling of alkenyl sulfonates with

MeMgX13,27-31

In view of these favorable attributes, it may not come as a surprise that

this chemistry was rapidly embraced by the academic and industrial
community.14-18 The selected larger scale applications shown in Figure 3 are
instructive and illustrate the current state of the art.19-26

Org. Synth. 2019, 96, 1-15 3 DOI: 10.15227/orgsyn.096.0001

 Figure 3. Applications on larger scale19-26

Our initial reports had already shown that aryl triflates and even
(electron-deficient) aryl tosylates can be cross coupled with alkyl-Grignard
reagents in good to excellent yields using Fe(acac)3 as a simple yet efficient
precatalyst (cf. Figure 1).8,9 Alkenyl sulfonates followed shortly thereafter
(Figure 2);13,27,28 a recent Org. Synth. procedure further illustrates their
utility.29 Building on these lead discoveries, the scope of the reaction was
explored30-33 and other viable leaving groups were identified, including
phosphonates,23,32,34-37 sulfamates,32,38,39 carbamates,38,62 carboxylates,40,64
trialkyl ammonium salts,65 and even various (thio) ethers.61,63 A few selected
examples are compiled in Table 1.
Although the cost of the iron salt is hardly a limiting factor, attempts
were made to lower the loading; applications using £ 1 mol% are not
uncommon.20,41,42 Non-hygroscopic and hence practical Fe(acac)3 is the most
popular precatalyst; in certain cases, other salts such as FeCln (n = 2, 3),
FeF3×3H2O,38,49 or iron thiolates43 show better performance. Likewise,
numerous iron complexes (formed ex situ or in situ) show good application
profiles.
NMP remains the preferred co-solvent for iron-catalyzed cross coupling
reactions (although certain reactions work better in its absence). This
compound, however, is potentially repro-toxic. Therefore many attempts
were made to avoid its use altogether or substitute NMP by more benign
additives, solvents or ligands.6,29,44,45,54 Among them, cyclic ureas such as
N,N-dimethylimidazolidin-2-one (DMI)55 and various (di)amines, especially
TMEDA (N,N,N’,N’-tetramethylethylenediamine),29,46-48 are most common;
their use, however, often mandates slow addition of the Grignard reagent to
the reaction mixture. Moreover, numerous reports rely on the use of NHC’s
or (chelating) (di)phosphines.49-53

Org. Synth. 2019, 96, 1-15 4 DOI: 10.15227/orgsyn.096.0001

Table 1. Iron-catalyzed cross coupling: Representative examples
Substrate Product Yield Ref.

O O
PMB PMB
N Cl N Me 80% 56
O O
S S
O O
O 78% 57
CN COOEt
EtOOC EtOOC
N
Cl 71% (X = O)
Cl N N
Cl 58
82% (X = NH)

X X 86% (X = S)

OPh
O Me
P OPh
O O
O
<87%[a] 59

COOtBu COOtBu

O
O P
OEt OAc 83%[b,c] 26
OEt

O
OTs
OR OR 78% 60
COOEt COOEt
R = TBS R = TBS

Ph 67% 61
Ph
OPh
F
O
O O
79% 62
OBn
Me2N O OBn

SPh 74% 63
OMe

F
O NMe2
S
91%[d] 39
O O

OAc C6H13

86% 64
O O O O

TfO
O O
Me3N 89% 65
OEt OEt

[a] using Me3ZnMgBr in THF at –78°C; [b] using 0.1 mol% of Fe(acac)3; [c] after acetylation;
[d] using FeF33H2O (10 mol%), IPrHCl (20 mol%), THF, reflux

Org. Synth. 2019, 96, 1-15 5 DOI: 10.15227/orgsyn.096.0001

 These advances notwithstanding, some important limitations also need
to be mentioned. In contrast to palladium-catalyzed cross coupling
reactions, which excel when it comes to the formation of C(sp2)-C(sp2) or
C(sp2)-C(sp) bonds, most notably aryl-aryl bonds, iron catalysis is currently
much less adequate for this very purpose; competing homo-coupling of the
Grignard reagent limits the scope. Although advances have been reported, a
general solution that truly rivals palladium (or nickel) catalysts in this
particularly important field of applications currently remains
elusive.9,38,39,49,66-68,75
The fact that Grignard reagents are privileged nucleophiles denotes an
advantage and a serious limitation at the same time. They are cheap and
industrially viable but obviously limited with regard to functional group
compatibility. Yet, the exceptional rate of many iron-catalyzed cross
coupling reactions partly mitigates this shortcoming: thus, a number of
substrates has been successfully engaged, which carry electrophilic
substituents that might not subsist in the presence of organomagnesium
reagents otherwise. Without claim to be complete, the list includes: alkyl-
and aryl halides, amides, carbamates, enoates, epoxides, esters, isocyanates,
ketones, nitriles, sulfonates, sulfonamides, thio-carbamates; such kinetic
selectivity, however, is potentially case-dependent. Therefore the need
persists to enlarge the portfolio of adequate nucleophiles. Encouraging
results have been obtained with organomanganese,69,70 -zinc,59,71-73
-lithium,74 -copper,75 and -boron reagents.76-80
In this context, it is pointed out that alkyl/aryl cross coupling can also
be effected without preparing a Grignard reagent in a separate step.81,82 As
an example, treatment of a mixture of cyclopentyl bromide and 1-bromo-2-
(trifluoromethyl)benzene with magnesium and catalytic amounts of FeCl2 in
THF/TMEDA at ambient temperature afforded 1-cyclopentyl-2-
(trifluoromethyl)benzene in 67% yield on up to 60 kg scale (Figure 3).83 As
the Grignard reagent transiently formed is directly consumed, large
concentrations will not be build-up at any point in time.

Non-Canonical Cross Coupling

The promise that cheap and benign iron catalysts allow palladium to be
substituted - at least in certain cross coupling reactions - was (and is) a
major incentive.6,8,9 It soon became clear, however, that this metal is also able
to promote cross coupling reactions of substrates that have little or no
precedent in the classical canon.

Org. Synth. 2019, 96, 1-15 6 DOI: 10.15227/orgsyn.096.0001

 The readiness with which primary and secondary alkyl halides
participate in iron-catalyzed cross coupling with arylmagnesium halides
and other nucleophiles illustrates the point.47,48,50,51,84-91 The functional group
tolerance is remarkable and even sterically hindered alkyl halides usually
react well (Table 2). Moreover, exploratory studies showed that asymmetric
enantioconvergent cross coupling of racemic secondary alkyl halides is
possible with iron catalysts bearing chelating diphosphine ligands that are
chiral at phosphorus (Scheme 1).92

Scheme 1. Pioneering study into asymmetric iron-catalyzed aryl/alkyl

cross coupling92

Even less conventional substrates work well (Table 2). 1-

Alkynylcyclopropyl tosylates, for example, react with Grignard reagents in
the presence of Fe(acac)3 cat. under net propargylic substitution;112 this
striking result illustrates that even tertiary alkyl electrophiles can be
successfully engaged in iron-catalyzed cross coupling.52,112 Yet, this pattern
contrasts the behavior of most other propargylic compounds, which usually
afford allenes by SN2’ type substitution reactions (except for some propargyl
bromides).93-97,113 For propargylic epoxides it was shown that the RMgX
reagent approaches syn to the O-atom, whereas organocopper reagents
deliver the R-substituent anti to the leaving group.95,113
An unconventional cross coupling reaction is manifest in the conversion
of lactone-derived gem-dichloroalkenes into non-terminal alkynes (Scheme
2).98-100 Note that the R-group of the organolithium reagent is incorporated
into the product as the substituent capping the alkyne; this transformation
likely proceeds via carbenoid intermediates. Even more involved cross
coupling “cascades” are known in the literature (Scheme 2).101,102

Org. Synth. 2019, 96, 1-15 7 DOI: 10.15227/orgsyn.096.0001

Table 2. Iron-catalyzed cross coupling of unorthodox electrophiles
Substrate Product Yield Ref.

OTES OTES

OBn O OBn 84% 103

O MeO
MeO
O OTES O OTES

OTES OTES

OTBS
OTBS
80% 104
N
I

R R
N N
67% {R = CHPh2) 105,106
I Ph 64% (R = Cbz)

MeO MeO
77%[a] 107
I
O O

O Br O Ph
AcO AcO
96%[a,b] 108,109
AcO OAc AcO OAc
OAc OAc

F F F F
62% 110
Br SO2Ph Ph SO2Ph

O O O O
S F S F
81%[b] 111
N H F H F

Ph Ph 70% 112
OTs Me

O HO
94% 113
C5H11
syn:anti = 10:1
93% ee C5H11 93% ee (syn)

SO2Cl
64% 114

SO2Ph
OiPr 62% 115

[a] using an iron diphosophine complex as precatalyst; [b] using Ar2Zn

Org. Synth. 2019, 96, 1-15 8 DOI: 10.15227/orgsyn.096.0001

 Scheme 2. Some unorthodox iron-catalyzed “cross coupling”
reactions99,101,102,118

The iron-catalyzed ring opening/cross coupling of 2-pyrone derivatives

is fairly unique.116 In a formal sense, the enol ester moiety embedded into
the heterocyclic ring serves as a leaving group. The available mechanistic
evidence, however, suggests that the iron catalyst formed in situ does not
insert into the C-O bond; rather, coordination to the pyrone p-system is
thought to trigger a 1,6-addition/ring opening cascade. Whether the ring
opening step itself is an electrocyclic process or follows an ionic mechanism
remains to be firmly established. In any case, this chemistry is compatible
with functional groups and various donor sites; it gives access to non-
thermodynamic dienoates that are difficult to make in isomerically pure
form otherwise. A late-stage application during the total synthesis of the
potent anticancer agent pateamine A illustrates this aspect (Scheme 2). 117,118
This Discussion Addendum cannot provide a comprehensive treatise of
iron-catalyzed cross coupling, broadly defined;14-18 rather, the chosen
examples are meant to illustrate the tremendous advances in the field since

Org. Synth. 2019, 96, 1-15 9 DOI: 10.15227/orgsyn.096.0001

the original Org. Synth. procedure was published in 2005. Although further
growth can be safely anticipated, iron catalysis at large awaits better
mechanistic understanding.2 The massive analytical challenges
notwithstanding, substantial recent progress provides an encouraging
outlook.119,120

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Alois Fürstner is a native of Austria. He

obtained his doctoral degree in 1987 from the
Technical University Graz (Prof. H.
Weidmann), Austria. After a postdoctoral
stint with the late Prof. W. Oppolzer in
Geneva, Switzerland, and a Habilitation in
Graz, he joined the Max-Planck-Institut für
Kohlenforschung (1993), Mülheim, Germany,
where he was promoted to the rank of
Director in 1998.

Org. Synth. 2019, 96, 1-15 15 DOI: 10.15227/orgsyn.096.0001