Iron-Catalyzed Reactions of 2-Pyridone Derivatives: 1,6-Addition and Formal Ring Opening/Cross Coupling

Article abstract of DOI:10.1002/asia.201900865

In the presence of simple iron salts, 2-pyridone derivatives react with Grignard reagents under mild conditions to give the corresponding 1,6-addition products; if the reaction medium is supplemented with an aprotic dipolar cosolvent after the actual addition step, the intermediates primarily formed succumb to ring opening, giving rise to non-thermodynamic Z,E-configured dienoic acid amide derivatives which are difficult to make otherwise. Control experiments as well as the isolation and crystallographic characterization of a (tricarbonyl)iron pyridone complex suggest that the active iron catalyst generated in situ exhibits high affinity to the polarized diene system embedded into the heterocyclic ring system of the substrates, which likely serves as the actual recognition element.

Full text of DOI:10.1002/asia.201900865

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Iron Catalyzed Reactions of 2-Pyridone Derivatives: 1,6-Addition
and Formal Ring Opening/Cross Coupling
Authors: Alois Fürstner, Lin Huang, and Yiting Gu
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10.1002/asia.201900865
Chemistry - An Asian Journal
Iron Catalyzed Reactions of 2-Pyridone Derivatives: 1,6-Addition and Formal
Ring Opening/Cross Coupling
Lin Huang, Yiting Gu, and Alois Fürstner*
Dedicated to Prof. Henry N. C. Wong on the occasion of his 70th birthday
Abstract: In the presence of simple iron salts, 2-pyridone derivatives react with Grignard reagents
under mild conditions to give the corresponding 1,6-addition products; if the reaction medium is
supplemented with an aprotic dipolar cosolvent after the actual addition step, the intermediates
primarily formed succumb to ring opening, giving rise to non-thermodynamic Z,E-configured dienoic
acid amide derivatives which are difficult to make otherwise. Control experiments as well as the
isolation and crystallographic characterization of a (tricarbonyl)iron pyridone complex suggest that
the active iron catalyst generated in situ exhibits high affinity to the polarized diene system
embedded into the heterocyclic ring system of the substrates, which likely serves as the actual
recognition element.
*
Dr. L. Huang, Y. Gu, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
Email: fuerstner@kofo.mpg.de
Supporting Information for this article can be found on the WWW under ###############
1
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Introduction
During our investigations into cross coupling, cycloaddition and cycloisomerization reactions using
cheap, practical, non-toxic and benign iron catalysts,1,2,3,4 we discovered that 2-pyrones A undergo an
unusual transformation when treated with Grignard reagents in the presence of catalytic Fe(acac)3 at
low temperature (Scheme 1). These substrates swiftly convert into dienoic acid derivatives E by what
appears to be a ring opening/cross coupling reaction, in which the enol ester subunit of the
heterocyclic ring formally gains the role of a leaving group that is replaced by the incoming
nucleophile with retention of configuration.5 Uncatalyzed attack of the organomagnesium reagent on
the lactone carbonyl group of A is too slow to be competitive6 and the non-thermodynamic Z,E-
configured 1,3-diene motif of the resulting product E usually persists under the mild conditions.7
Moreover, the low-valent iron catalyst generated in situ proved compatible with numerous
functional groups, including heteroatom donor sites that interfere with more traditional cross
coupling. For its favorable profile and the ready availability of differently substituted pyrone
derivatives,8,9 this unorthodox transformation laid the ground for concise approaches to the marine
natural product pateamine A and its almost equipotent analog DMDA-Pat A, in that it allowed the
very sensitive but critically important dienoate subunit of these highly cytotoxic agents to be
unveiled at a late stage from a robust heterocyclic precursor.10,11
Indirect evidence, however, suggested that the net outcome of the reaction is probably not the result
of a true cross coupling manifold; rather, the reaction is thought to proceed via an initial 1,6-addition
followed by ring opening of the resulting intermediate of type C or D.5,10,12 This latter step could
proceed in an electrocyclic or ionic fashion; in any case, it must be fast and facile even at low
temperature, because the proposed intermediates defied all attempts at characterization. Provided
that this mechanistic hypothesis is valid, is should be possible to engage other heterocyclic
compounds containing a polarized diene entity into similar transformations.
2
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Scheme 1. Iron catalyzed formal ring opening/cross coupling of pyrones
Results and Discussion
2-Pyridones are obvious and relevant candidates:13,14,15 the enamide embedded in their ring system is
certainly not a privileged subunit for classical cross coupling via oxidative insertion/reductive
elimination, whereas an iron catalyzed 1,6-addition is feasible since acyclic α,β,γ,δ-unsaturated
amides have previously been shown to react with aryl-Grignard reagents in the presence of catalytic
amounts of FeCl2 with high selectivity.16,17 Indeed, the N-benzylated substrate 1, on treatment with
PhMgBr and Fe(acac)3 (5 mol%), gave product 2a in which the heterocyclic ring is intact (Table 1);
under optimized conditions (THF, 45°C), the yield was almost quantitative (entry 6). Fe(acac)3,
Fe(acac)2 and FeCl3 work almost equally well,18 whereas the reaction did not proceed with FeF3 or in
the absence of an iron precatalyst.19
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Table 1. Reaction Optimization and Gathering of Mechanistically Relevant Information (entries 10-15,
see below)[a]
Entry
FeXn
Solvent
T (°C)
2[b]
1
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
FeCl3
Et2O
Et2O
Et2O
toluene
THF
78
19
2
45
69
46[c]
3
20
4
45
78
5
45
94 (83)[d]
96[e,f]
93
6
THF
45
7
THF
45
8
FeF3
THF
45
n.r.
89
9
Fe(acac)2
[(Me4Fe)∙(MeLi)][Li∙(OEt2)]2
Fe(CO)5
THF
45
10
11
THF
45  RT
45  RT
78
THF
78
12
13
THF
THF
45  RT
45  RT
65
99
14
THF
THF
45  RT
45  RT
45
75
15
[a]
[b]
unless stated otherwise, all reactions were carried out using PhMgBr (3 equiv.); determined by
[c]
NMR, unless stated otherwise; small amounts of unidentified byproducts were detected in the
crude mixture; [d] using PhMgCl; [e] isolated yield; [f] using only 1.5 equivalents of PhMgBr
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Scheme 2. Scope of the iron catalyzed 1,6-addition reaction to 2-pyridones; unless stated otherwise,
all reaction were performed with RMgBr (1.5 equiv.), Fe(acac)3 (5 mol%) in THF at 45°C; [a] with 3
equiv. of RMgX; [b] at 20°C; [c] at 45°C to RT;
Scheme 3. Iron catalyzed three component coupling reactions
As evident from the examples shown in Scheme 2, the reaction is tolerant of different polar and
apolar functionalities in the substrate as well as in the Grignard reagent. The arguably most notable
case is product 6 derived from 1-benzyl-5-bromopyridin-2(1H)-one: the fact that the bromide
substituent persists under the chosen reaction conditions implies that the iron catalyzed addition
reaction to the heterocyclic ring is even faster than a regular iron catalyzed cross coupling, although
the latter process is known to proceed very rapidly at low temperatures;20,21,22,23 such stunning
“inverse” chemoselectivity is exceedingly rare.24 Since spontaneous ring opening did not occur, it was
also possible to intercept the enolate primarily formed by 1,6-addition with an appropriate
electrophilic partner (Scheme 3). The high yielding preparation of compounds 11a,b illustrates this
point (for the structure of compound 11a in the solid state, see the SI). Once again it is remarkable
that the iron catalyzed 1,6-additon to the 2-pyridone outcompetes the uncatalyzed reaction of the
Grignard reagent with the (aromatic or aliphatic) ester present in the mixture; likewise, the reaction
5
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is faster than cross coupling with the chloride substituent of methyl chlorobenzoate used to make
11a, which is known to be an excellent substrate otherwise.25,26,27
Scheme 4. a) MeMgBr, Fe(acac)3 (5 mol%), Et2O, 30°C, 93%; b) BnNH2, HOBt, EDCHCl, Et3N, CH2Cl2,
DMF, 92%; c) LiHMDS, DMF, 100°C, 67%; EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;
HOBt = 1-hydroxybenzotriazole; LiHMDS = lithium hexamethyldisilazide
Scheme 5. a) PhMgBr, Fe(acac)3 (5 mol%), Ph3P (10 mol%), Et2O, 30°C, 62%; b) DMF, 30°C 
10°C, 60% (over both steps), Z,E:E,E  15:1
Figure 1. Structure of compound 17 in the solid state; H-atoms are omitted for clarity
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Figure 2. Structure of compound 18a in the solid state; H-atoms are omitted for clarity
These results are consistent with a 1,6-addition reaction as the actual iron catalyzed event; it
remained to be clarified, however, why this step is followed by instantaneous ring opening in the
pyrone series but not with 2-pyridones such as 1. To this end, we transformed the pyrone-derived
dienoic acid 13 into the corresponding amide 14 (Scheme 4); on deprotonation with LiHMDS and
warming of the resulting mixture, 14 cyclized to the corresponding dihydropyridin-2-one 15. Since
this control experiment suggested that the cyclic form is thermodynamically more stable in this case,
attempts were made to change the tip in favor of the ring opened product by altering the N-
substituent. Based on literature precedent,28 the N-tosyl derivative 16 was deemed adequate (the
structure of 16 in the solid state is contained in the SI) (Scheme 5): initially, however, only the 1,6-
adduct 17 was attained on reaction with PhMgBr and catalytic Fe(acac)3. Under standard conditions,
the conversion remained incomplete, but the outcome could be improved in the presence of PPh3
(10 mol%) in Et2O as the solvent. Although the dihydropyridone ring of 17 is hardly puckered, the
phenyl substituent is axially oriented to avoid eclipsing with the adjacent N-Ts group (Figure 1).29
Interestingly, addition of DMF to the crude mixture and raising the temperature from 30°C to 10°C
entailed the expected ring opening with formation of amide 18a in respectable yield and excellent
geometrical purity in favor of the non-thermodynamic Z,E-diene isomer;30 this stereochemical
assignment was confirmed by single crystal X-ray diffraction (Figure 2). The additional examples
compiled in Scheme 5 show that this method has a reasonable scope and provides access to products
that are difficult to make otherwise.
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Scheme 6. Preparation of the homoleptic iron pyrone complex 22 and examination of its catalytic
competence; in the solid state, the unit cell of 22 contains an additional but unbound molecule of 12

Figure 3. Structure of the Lewis acid/Lewis base adduct 22 in two different orientations; the BF4
counterions as well as an additional cocrystallized but unbound molecule of 12 are not shown for
clarity; the full structure is contained in the SI
The data outlined above leave little doubt that the observed ring opening/cross coupling of 2-pyrone
and 2-pyridone derivatives is the net outcome of two consecutive steps: of them, only the initial 1,6-
8
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additon is thought to proceed under the aegis of an iron catalyst, whereas the actual ring cleavage is
most likely an uncatalyzed event, which is much more facile for 2-pyrones than for N-tosylated 2-
pyridones.30 To gain further insights, we studied the interaction of such substrates with various iron
sources. The Fe(+2) or Fe(+3) precatalyst is supposed to act as a simple Lewis acid that binds to the
more accessible lone pair of the carbonyl group: using an ionized Fe(+2) salt, we managed to obtain a
homoleptic adduct that is stable enough to be isolated and catalytically competent (Scheme 6). The
structure of complex 22 in the solid state (Figure 3) shows an octahedral environment comprised of
six 2-pyrone ligands about the iron center.31 The Newman-type projection along the O1Fe1O1*
axis reveals an interesting organization of the heterocyclic rings via -stacking (distance between the
centroids of the pyrone rings occupying the equatorial positions, 3.53 Å). All lactone carbonyl groups
(for example, O1C1 1.233(2) Å) are elongated by coordination to the Lewis-acidic cation relative to
that of the parent pyrone 12 (O1C1 1.212(1) Å; the structure of 12 in the solid state is contained in
the SI).
Scheme 7. a) Fe(CO)5, Bu2O/THF (5:1), 65°C, 19% (23); 21% (24)
Figure 4. Structure of the pyrone tricarbonyliron complex 23 in the solid state
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Figure 5. Structure of the pyridone tricarbonyliron complex 24 in the solid state
Although such coordination to an Fe(+2) center certainly activates the carbonyl group and also
enhances the vinylogous Michael acceptor properties of the pyrone, it is unlikely that this canonical
Lewis acid/base interaction renders the observed 1,6-additon so astoundingly facile. Extensive
screening in this laboratory showed that iron is almost uniquely capable in catalyzing this
transformation.32 Since iron salts react instantly with polar organometallic reagents to give ate-
complexes33,34,35,36 and/or low valent iron species,34,37,38 the reasons for the unusually facile addition
to pyrones and pyridones are likely rooted in a more specific affinity to substrates of this kind. It is,
however, exceedingly difficult to establish the nature of the active species generated in situ, not least
because low valent organometallic iron complexes are highly sensitive, often paramagnetic, and tend
to “age” rapidly; moreover, the exact speciation is strongly dependent on the chosen conditions and
the presence/absence of polar additives in the mixture.39 The mechanistic complexity of the current
system is reflected in a number of control experiments, which showed that several well-defined but
structurally quite distinct iron species are competent (pre)catalysts (see Table 1): thus, the intricate
Fe(+2)-ate complex [(Me4Fe)∙(MeLi)][Li∙(OEt2)]2 (entry 10),33 two different Fe(0) olefin complexes
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(entries 14, 15),37,40 and even catalytic amounts of Fe(CO)5 (entry 11) or the derived pyridone
complex (entry 12) worked well. In contrast to the oxophilicity of Fe(+2) and Fe(+3) salts, many low-
valent iron species are inherently carbophilic; 1,3-dienes are amongst the privileged ligands which
get activated toward attack by certain nucleophiles, for example, upon coordination to the [Fe(CO)3]
fragment.41,42,43 Therefore it seemed likely that the polarized diene motif embedded into the pyrone-
or pyridone rings constitutes the critical recognition element for the active catalyst. While attempted
complexation of 12 or 16 with either [CpFe(C2H4)2][Li(tmeda)]40,43 or [dippp)Fe(C2H4)2]37,43 failed to
afford single crystals suitable for X-ray diffraction, Fe(CO)5 served this purpose well. In this context, it
is important to note that (tricarbonyl)iron complexes of 2-pyrones had previously been found
susceptible to nucleophilic attack at the carbonyl group rather than at the enol ether site,44,45
whereas we consider them to be valid models for the reactive intermediate accountable for iron
catalyzed 1,6-addition.10 Under this premise, 2-pyridones should be amenable to analogous -
complexation in order to explain why they react analogously; this is indeed the case (Scheme 7).
Figures 4 and 5 illustrate that adduct formation entails massive distortions in both series. Back-
bonding from the low-valent metal center into the * orbitals of the 4-bound heterocyclic ligand is
manifest in the massive elongation of the C4C5 bond (1.418(5) Å) in pyrone complex 23 versus
1.340(1) Å in unbound pyrone 12; the effect is even stronger in the pyridone complex 24 (C4C5
1.436(2) Å in versus 1.343(2) Å in free 16). As expected, the C3C4 bond is somewhat contracted
(1.403(5) Å in 23 versus 1.427(1) Å in the 12; 1.397(2) Å in 24 versus 1.420(3) Å in 16). Since neither
2-pyrones nor 2-pyridones show significant aromatic character, these heterocycles are torsionally
flexible. In fact, the lactone (lactam) moiety is forced out of co-planarity with the olefinic -system;
as a result, orbital overlap is disrupted and the enol ether (enamide) character lost, at least in part.
The incipient carbenoid nature of C5, which carries a carbon-metal and a leaving group, is
unmistakable in the structures of complexes 23, 24 and related complexes10,45 in the solid state.
Delivery of an R-group from a putative loaded iron center to the C5 position becomes not only
feasible but likely facile,46 very much in line with our experimental findings. The concomitant
formation of an (iron) enolate enhances the regiochemical course of the reaction and provides an
additional driving force; this enolate formation is also “precast” in the structures of 23 or 24, because
the C2C3 bond of the pyrone (pyridone) ligand has already lost much of its former double bond
11
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character (1.435(6) Å in 23 versus 1.358(1) Å in 12; 1.438(2) in 24 versus 1.351(3) Å in 16) and a
carbon-metal bond is also looming. Hence, adducts of this type seem to be ideally set up for
regioselective transfer of a hydrocarbyl residue from the loaded iron center to the heterocyclic ligand
framework.
Scheme 8. a) PhMgBr, Fe(acac)3 (5 mol%), Ph3P (10 mol%),, Et2O, 30°C, then DMF 30°C  RT, 60%;
b) MeMgBr, Fe(acac)3 (5 mol%), Et2O, 30°C, 86%; c) PhMgBr, Fe(acac)3 (5 mol%), Et2O, 30°C, 44%;
d) MeMgBr, Fe(acac)3 (5 mol%), Et2O/toluene (1:1), 30°C, 93%
The available experimental evidence is less clear with regard to the subsequent ring opening step.
Yet, two pieces of evidence seem to advocate for an ionic rather than electrocyclic mechanism: as
outlined above, the addition of DMF is necessary to entail ring cleavage in the pyridone series;
pericyclic processes in general, however, are not expected to show such a strong solvent
dependence.47,48 A perhaps more stringent argument can be seen in the stereochemical course of the
reactions (Scheme 8): the outward rotation of the phenyl groups during the opening of 16 and 25 to
give 18a and 27, respectively, would be in line with the torquoselective preference of this
substituent, but the exclusive inward orientation of the methyl group in 26 violates the established
selectivity rules of electrocyclic processes;49 the selective formation of 18a and 27 is hence more
likely thermodynamic in origin (the structure of 27 in the solid state is contained in the SI). Product
29, the double bond geometry of which mirrors the stereostructure of the substrate, is arguably an
12
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even more stringent case:5 an electrocyclic opening of an intermediate of type C would hardly entail
formation of a single stereoisomer since the two relevant substituents (Me versus Et) have the same
electronic character and are similar in size. Rather, this outcome suggests that some stereochemical
communication between the breaking CO bond and the metal center is operative in the
stereodetermining step, as tentatively drawn in D. We appreciate, however, that further
experimental and computational scrutiny is needed to either confirm or disprove this view.
Conclusions
The present study extend the structural space covered by iron catalyzed CC-bond formation in
general and the rather unconventional formal ring opening/cross coupling in particular. Although not
all mechanistic questions could be answered in full detail, the available data show that the high
affinity of low-valent iron catalysts to (polarized) dienes constitutes a formidable driving force which
can likely be exploited in different context too. Further efforts at leveraging this and other as yet
untapped opportunities of homogeneous iron catalysis for organic synthesis are underway and will
be reported in due course.50
Acknowledgements
Generous financial support by the ICIQ International Ph. D. Mobility Program (Severo Ochoa
Excellence Accreditation, Spanish Ministerio de Economia y Competitividad, predoctoral fellowship
for Y. G.) and the MPG is gratefully acknowledged. We thank Mr. J. Rust and Prof. C. W. Lehmann for
solving the X-ray structures and the analytical departments of our Institute for excellent support of
our program.
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For the Table of Contents
Keep it closed or lock it open: The unique ability of simple iron salts to catalyze the 1,6-addition of
Grignard reagents to 2-pyridones is likely due to the affinity of the active iron species generated in
situ to the polarized diene subunit of the substrates. When the reaction medium is complemented
with an aprotic dipolar cosolvent, CC bond formation is followed by opening of the heterocyclic
ring.
Keywords: 1,6-addition • cross coupling • dienes • heterocycles • iron catalysis • ring cleavage
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1
A. Fürstner, ACS Centr. Sci. 2016, 2, 778-789.
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C.-L. Sun, A. Fürstner, Angew. Chem. Int. Ed. 2013, 52, 13071-13075; Angew. Chem. 2013, 125,
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Addition to the lactone group of 2-pyrones proceeds readily otherwise, see: a) R. Gompper, O.
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7
Scrambling does occur upon warm-up or in the presence of nucleophilic additives or solvents;
therefore the proper choice of the reaction medium is critically important, see ref. 5,10.
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6155-6160.
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12
Certain stabilized carbanions such as cyanide react with 2-pyrones via 1,6-addition/ring
opening, although the substrate scope is exceedingly narrow and the stereoselectivity strongly
dependent on the chosen conditions, see: a) G. Vogel, J. Org. Chem. 1965, 30, 203-207; b) A. R.
Frisbee, M. H. Nantz, G. W. Kramer, P. L. Fuchs, P. L. J. Am. Chem. Soc. 1984, 106, 7143-7145;
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9, 22-32.
15
16
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Fe(acac)3 (99.9+% purity) is the pre-catalyst of choice because it is cheap, non-hygroscopic and
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19
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