FeCl3 as an Ion-Pairing Lewis Acid Catalyst. Formation of Highly Lewis Acidic FeCl2+ and Thermodynamically Stable FeCl4- to Catalyze the Aza-Diels-Alder Reaction with High Turnover Frequency

Article abstract of DOI:10.1021/acs.orglett.8b03249

The aza-Diels-Alder reaction of nonactivated dienes and imines was realized through the action of the ion-paired Lewis acid catalyst [FeCl₂]⁺[FeCl₄]^- generated by the in situ disproportionation of FeCl₃. The uniquely high reactivity of [FeCl₂]⁺[FeCl₄]^- was attributed to both the highly Lewis acidic FeCl₂⁺ and thermodynamically stable FeCl₄^- acting as an ion-paired catalyst. Synchrotron-based X-ray absorption fine structure measurements provided fundamental insights into the disproportionation and structure of the resulting ion-paired iron complex. A theoretical study was performed to analyze the catalytic reaction and better understand the "ion-pairing effect" which transforms simple FeCl₃ into a high turnover frequency Lewis acid catalyst in the aza-Diels-Alder reaction of nonactivated dienes and imines.

Full text of DOI:10.1021/acs.orglett.8b03249

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
FeCl3 as an Ion-Pairing Lewis Acid Catalyst. Formation of Highly
+
−
Lewis Acidic FeCl2 and Thermodynamically Stable FeCl4 To
Catalyze the Aza-Diels−Alder Reaction with High Turnover
Frequency
Rei Tomifuji, Kazuki Maeda, Toshifumi Takahashi, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
S
* Supporting Information
ABSTRACT: The aza-Diels−Alder reaction of nonactivated
dienes and imines was realized through the action of the ion-
paired Lewis acid catalyst [FeCl2]+[FeCl4]− generated by the
in situ disproportionation of FeCl3. The uniquely high
reactivity of [FeCl2]+[FeCl4]− was attributed to both the
+
highly Lewis acidic FeCl2 and thermodynamically stable
−
FeCl4 acting as an ion-paired catalyst. Synchrotron-based X-
ray absorption fine structure measurements provided fundamental insights into the disproportionation and structure of the
resulting ion-paired iron complex. A theoretical study was performed to analyze the catalytic reaction and better understand the
“ion-pairing effect” which transforms simple FeCl3 into a high turnover frequency Lewis acid catalyst in the aza-Diels−Alder
reaction of nonactivated dienes and imines.
Scheme 1. Disproportionation of FeCl3
nderstanding the unique character of first-row transition
Umetals as abundant, nontoxic metal catalysts has become
an important topic of research since such fundamental findings
can help develop new transformations that can realize the
practical chemical production of valuable organic materials.1
Herein, we report that readily available FeCl3 shows high Lewis
acidity as a catalyst for the aza-Diels−Alder reactions of
nonactivated dienes and imines to provide tetrahydropyridines.
Although recognized as a simple reaction, it is, in fact, difficult
to accomplish due to the low energy level of the HOMO of the
diene (compared to those of activated dienes such as the
Danishefsky and Rawal types) as well as the high energy level
of the imine LUMO. Thus, the development of a practical
Lewis acid catalyst with a high turnover frequency (TOF) for
convenient transformation is still in demand.2 Furthermore,
considering that a late-stage aza-Diels−Alder reaction with a
nonactivated diene and imine could be a powerful tool that
would offer an alternative strategy for the total synthesis of
natural compounds and manufacture of medicinal drugs, the
development of a new catalyst that promotes the highly
chemoselective reaction based on an abundant, nontoxic metal
would be quite desirable.
Swanson and Laurie originally described the disproportio-
nation of FeCl3 upon the coordination of polar solvents such as
DMF and pyridine (Scheme 1).3 On the basis of their findings,
FeCl3 disproportionation has been applied to generate reactive
oxidation catalysts in organic synthesis, as exemplified by the
independent seminal works of Tobinaga, Frazier, Jr., Over-
mann, and MacMillan.4 We envisioned that the disproportio-
nation of FeCl3 would also be triggered upon coordination
with an imine, e.g., as the dienophile in the aza-Diels−Alder
reaction, instead of a polar solvent molecule, forming the
+
highly Lewis acidic FeCl2 species along with the thermody-
−
namically stable FeCl4 . Consequently, the LUMO of the
imine would be lowered and the dienophile’s reactivity with a
nonactivated diene would be enhanced to accomplish a simple,
convenient metal-catalyzed aza-Diels−Alder reaction. To prove
our hypothesis, we initially examined the Lewis acidity of FeCl3
via IR spectroscopy, measuring the carbonyl stretching
vibration of its 2,6-dimethyl-γ-pyrone complex in nonpolar
solution (Figure 1),5 where a larger shift (ΔνCO) in the
carbonyl absorption peak indicates higher Lewis acidity. In the
event, FeCl3, which disproportionates to [FeCl2]+[FeCl4]−,
shows high Lewis acidity relative to various common Lewis
acids. Encouraged by these results, we next investigated the
disproportionation of FeCl3 upon coordination with N-
sulfonylated imine 1a, which contains a Lewis basic oxygen
atom to coordinate with the Lewis acid (Scheme 2). The
disproportionation and formation of ion-paired complex
[FeCl2(1a)2]+[FeCl4]− (CP1) was confirmed spectroscopi-
cally. Formula determination by MALDI-MS was consistent
Received: October 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03249
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Letter
Figure 2. Solution-phase Fe K-edge EXAFS analysis (Fourier
transform of k3-weighted spectrum: experimentally determined
(solid line) and FEFF-calculated fitting of DFT model CP1 (dashed
line).
To assess the catalytic reactivity of in situ generated CP1, we
next examined the aza-Diels−Alder reaction of imine 1a and
diene 2a in the presence of FeCl3 in toluene at 25 °C for 2 h
(Figure 3). The reaction afforded cycloadduct 3aa in almost
Figure 1. IR CO stretching vibration analysis. (a) 2,6-Dimethyl-γ-
pyrone with 1 equiv of Lewis acid. (b) MAD: methylaluminum
bis(2,6-di-tert-butyl-4-methylphenoxide). (c) With addition of an
equivalent amount of the 1-butyl-3-methylimidazolium salt
[Bmim]+[X]−.
Scheme 2. Disproportionation of FeCl3 upon Coordination
with Imine 1aTo Form Ion-Paired Complex
[FeCl2(1a)2]+[FeCl4]− (CP1)
Figure 3. Effect of Lewis acid catalysts on the aza-Diels−Alder
reaction of imine 1a with diene 2a. (a) Lewis acid (1 mol %), imine
1a (0.2 mmol), diene 2a (0.4 mmol), solvent (2 mL), 25 °C, 2 h. (b)
NMR yields. (c) Isolated yields. (d) Reaction for 1 h in
dichloromethane. (e) Reactions were carried out with the addition
of imidazolium salt [Bmim]+[X]− (1 mol %) in dichloromethane.
with that theoretically calculated for a cationic iron complex
with two imine and two chloride ligands, which is identical to
quantitative yield, even with 1 mol % catalytic loading. The
reaction with other Lewis acids such as AlCl3, MAD, B(C6F5)3,
and RuCl3 resulted in lower yields. To gain insight into the
− +
that of [M(CP1)−FeCl4 ] , i.e., [FeCl2(1a)2]+. Furthermore,
−
+
the UV−vis spectrum revealed the formation of FeCl4 by
disproportionation of FeCl3 to form cationic FeCl2 and
comparison with the spectrum for [Bmim][FeCl4] as a
reference compound. To gain further insight into CP1, Fe
K-edge X-ray absorption spectroscopy (XAS) was performed
using a synchrotron radiation beamline, where the ultrahigh
brightness made solution-phase XAS accessible for in situ
structural investigation. Analysis of the extended X-ray
absorption fine structure (EXAFS) spectrum of the solution
of FeCl3 with imine 1a in toluene clearly indicated good
agreement with the theoretically calculated CP1 model (Figure
2). A significant pre-edge peak in the X-ray absorption near
edge structure (XANES) also indicated the formation of an
iron species with tetrahedral geometry (Supporting Informa-
tion).6 Furthermore, a calculated absorption spectrum using
the finite difference method for postulated complex CP1
resulted in good agreement with the experimentally obtained
XANES spectrum. Based on these results, we confirmed that
the disproportionation of FeCl3 generates the highly Lewis
anionic FeCl4− in terms of catalytic reactivity, the reaction was
examined with FeCl3 in the presence of imidazolium salts
−
−
which possessed the counteranions Cl−, SbF6 , and FeCl4 .
The addition of Cl− dramatically retarded the reaction because
the excess Cl− coordinated with FeCl3 to form the stable but
−
−
inactive anion FeCl4 . In contrast, in the presence of SbF6 ,
the reaction proceeded without any inhibition of reactivity.
Notably, with the addition of FeCl4 , the reaction was not
−
−
impeded, since FeCl4 behaves as a noncoordinating anion.
These results are consistent with the aforementioned IR-based
Lewis acidity estimates for the 2,6-dimethyl-γ-pyrone-coordi-
nated iron complexes with or without imidazolium salts (the
last three rows in Figure 1). Therefore, the disproportionation
of FeCl3 concomitantly generates the strongly Lewis acidic
+
FeCl2 with coordination of imine 1a, which indeed facilitates
the aza-Diels−Alder reaction with nonactivated diene 2a. To
demonstrate the scope of the in situ generated CP1-catalyzed
aza-Diels−Alder reaction, we examined the reactions of various
imines 1 with conjugated dienes 2 (Figure 4). Under the
optimized reaction conditions, functional groups such as nitro,
ester, ether, and halogen groups were tolerated, giving the
+
acidic FeCl2 via the coordination of two imine molecules
along with the formation of the thermodynamically stable
−
FeCl4 , which leads to the in situ generation of ion-paired iron
complex CP1.
B
DOI: 10.1021/acs.orglett.8b03249
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Letter
FeCl3 forms CP1; then C−C bond formation with the addition
of diene 2a occurs with a Gibbs activation energy of 21.1 kcal/
mol via TS1, which is the TOF-determining transition state
(TDTS, vide infra). This is followed by cyclization to form the
C−N bond in an “energy-concerted bonding stepwise manner”
to afford CP2.7 The dissociation of 3aa from an iron atom
proceeds via coordination of another imine 1aa to form
thermodynamically stable five-coordination trigonal bipyrami-
dal complex CP3, which is the TOF-determining intermediate
(TDI, vide infra). Finally, cycloadduct 3aa is dissociated from
iron with small endergonic energy (2 kcal/mol) to regenerate
initial active species CP1′. To better understand how the
[FeCl2]+[FeCl4]− catalyst accelerates the addition of diene to
imine with TS1, we investigated the step electronically through
fragment molecular orbital (FMO) analysis (Figure 5b).8
During formation of the C−C bond at TS1, the dienyl HOMO
overlaps well with the imino LUMO (π*C−N antibonding
orbital). The population of the imino LUMO considerably
increases to 0.587 e in TS1, while the population of the dienyl
HOMO considerably decreases to 1.398 e. These results
clearly indicate that charge transfer (CT) substantially occurs
from the diene π orbital to the antibonding LUMO of the
imine. That is, this CT stabilizes the TS1 and increases the
electron population of the imine moiety, which contributes to
C−C bond formation. Next, the proposed catalytic cycle for
the aza-Diels−Alder reaction was analyzed by the energetic
span model.9 In this model, the TOF of the catalytic cycle can
be measured with the energetic span δG, which is the
difference in the Gibbs energy between the TOF-determining
transition state (TDTS) and the TOF-determining intermedi-
ate (TDI), with the addition of the global Gibbs energy of the
reaction when the TDTS appears before the TDI. TDTS and
TDI are the most unstable and most stable species in the
catalytic cycle, respectively. Therefore, δG is a genuinely
effective barrier of the global reaction in the catalytic cycle,
which can be subsequently used to estimate the TOF.
Calculated δG values for this reaction and other catalytic
systems are summarized in Figure 6, to compare the unique
catalytic reactivity of FeCl3 with analogous ion-paired catalysts
[AlCl2]+[AlCl4]− (via disproportionation of AlCl3)10 and
[RuCl2]+[RuCl4]− (via disproportionation of RuCl3), and
nonion-paired cationic iron catalyst [FeCl2]+ without [FeCl4]−.
The reaction with [AlCl2]+[AlCl4]− has slightly larger δG (27.5
kcal/mol) and slightly lower relative TOF (relTOF) values
compared to [FeCl2]+[FeCl4]−, which is mainly attributed to
the high energy TDTS involving the coordination of four
Figure 4. Aza-Diels−Alder reactions. (a) FeCl3 (1 mol %), imine 1
(0.2 mmol), diene 2 (0.4 mmol), toluene (2 mL), 2 h. (b) Isolated
yields. (c) 6 h. (d) FeCl3 (3 mol %), 25 °C, 6 h. (d) FeCl3 (5 mol %),
50 °C, 6 h.
corresponding substituted cycloadducts in high yields (3ba−
ia). These results highlight the excellent functional group
compatibility of the CP1-catalyzed reaction, which is ascribed
to the selective and substantial Lewis acid/base affinity of CP1
toward the oxygen atom on the N-sulfonylated imine. The
reaction using N-substituted imines with simple alkyl or aryl
substitutes resulted in low yields.
To understand the electronic character of the ion-paired
Lewis acid catalyst CP1 in the aza-Diels−Alder reaction, we
performed a series of DFT calculations. Based on spectro-
scopic observations, the [FeCl2(1a)2]+[FeCl4]− (CP1) species
formed via the coordination of two molecules of imine 1a to
FeCl3 was reasonably employed as the active species of this
catalytic reaction. The DFT calculations supported the
catalytic cycle involving the [FeCl2]+[FeCl4]− complex, as
shown in Figure 5a. First, the coordination of imine 1a to
Figure 5. (a) Calculated free energy profile for the transformation. (b) Important Kohn−Sham MOs (electron population and orbital energy) of
imine and diene moieties in TS1. (c) Natural bond orbital analysis in TS1.
C
DOI: 10.1021/acs.orglett.8b03249
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Letter
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kurahashi.takuya.2c@kyoto-u.ac.jp.
*E-mail: matsubara.seijiro.2e@kyoto-u.ac.jp.
ORCID
Takuya Kurahashi: 0000-0001-8417-7660
Seijiro Matsubara: 0000-0001-8484-4574
Notes
Figure 6. Energetic spans in several catalytic systems. (a) Gibbs free
energy (kcal/mol). (b) Energetic span (kcal/mol). (c) Relative
turnover frequency normalized to the value for [FeCl2]+[FeCl4]−.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
imine molecules to form [AlCl2(1a)4]+[AlCl4]− as the initial
active species with decreased Lewis acidity. The reaction with
[RuCl2]+[RuCl4]− has a very low-lying TDI (CP3) that results
in a large δG (34.7 kcal/mol) and low relTOF. This is
essentially because the ruthenium(III) complex has a longer
metal−ligand bond than iron(III), and thus, a thermodynami-
cally stable five-coordination trigonal bipyramidal geometry
with less steric repulsion is preferred. We also found that the
reaction of the [FeCl2]+ catalyst without a counteranion has an
energetically high-lying TDTS leading to a high δG (40.6 kcal/
mol). Therefore, in the ion-paired complex [FeCl2]+[FeCl4]−,
both [FeCl2]+ and [FeCl4]− promote the reaction efficiently by
lowering the TDTS and also raising the TDI, respectively,
narrowing the δG in the catalytic cycle. Of note, second-order
perturbation theory analysis in NBO basis for donor−acceptor
orbital interactions corresponding to the TS1 of
[FeCl2]+[FeCl4]− catalysis shows only faint orbital interactions
between [FeCl4]− and the remainder of the reacting fragment
(Figure 5c), suggesting that a long-range electrostatic
interaction dominates over the short-range orbital interaction
for thermodynamic stabilization to realize the low-lying
activation energy of TS1 as TDTS.
This work was supported by ACT-C from the JST (Japan) and
Grants-in-Aid for Scientific Research (Nos. 18H04253,
17KT0006, 16K13951, and 15H03809) from MEXT
(Japan). T.K. acknowledges the Asahi Glass Foundation. We
are grateful to Prof. Tsunehiro Tanaka (Kyoto University),
Prof. Masaharu Nakamura (Kyoto University), Prof. Hikaru
Takaya (Kyoto University), Dr. Tetsuo Honma (JASRI; Japan
Synchrotron Radiation Research Institute), Dr. Hironori
Ofuchi (JASRI), Dr. Masafumi Takagaki (JASRI), and Mr.
Kyohei Fujiwara (Ajinomoto Co., Inc.) for valuable support in
the XAS analysis at the BL14B2 beamline of the SPring-8
synchrotron radiation facility (Proposal Nos. 2018B1594,
2018A1690, 2017B1748, 2017A1700, 2016B1766,
2016A1680, 2016A1549, 2015B1770).
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+
acidic FeCl2 and thermodynamically stable FeCl4− that act as
the ion-paired catalyst [FeCl2]+[FeCl4]− after in situ
disproportionation upon imine coordination. The dispropor-
tionation was confirmed spectroscopically, and the catalytic
cycle was analyzed theoretically. The high TOF reactivity of
the catalyst was rationalized with the energetic span model;
[FeCl2]+[FeCl4]− realizes both a low-energy TOF-determining
transition state (TDTS) and a high-energy TOF-determining
intermediate (TDI). The obtained fundamental understanding
of this first-row transition metal Lewis acid catalyst will provide
new ideas for promoting catalytic reactions with high TOFs in
other reactions. Asymmetric Lewis acid catalyzed reactions
with high TOFs as a practical organic synthetic method should
also be realizable; these studies are currently under
investigation in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03249.
Experimental procedures; spectroscopic and analytical
data for new compounds (PDF)
D
DOI: 10.1021/acs.orglett.8b03249
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