Development of solvent-driven iron-catalyzed reactions

Article abstract of DOI:10.3987/REV-16-842

The possibility of solvent-driven iron-catalyzed reactions has been investigated using ionic liquids and acetonitrile as key solvents. Three iron-catalyzed reactions, the intramolecular cyclization of cyclopropane dithioacetals, the [2+2]-cycloaddition of (trans)-anethole, and the [2+3]-type cycloaddition of styrene derivatives with 1,4-benzoquinone, were first developed using acetonitrile as solvent in the presence of 3～5 mol% of Fe(ClO₄ )₃ ?Al₂ O₃ or Fe(BF₄ )₂ ?6H₂ O under air conditions. In particular, we found the rapid cycloaddition of iron-catalyzed [2+3]-type cycloaddition of styrene derivatives with 1,4-benzoquinone when the reaction was carried out in an ionic liquid which contained [PF₆ ] or [Tf₂N] anion. Homo-coupling reaction of aryl or alkynyl Grignard reagent was next discovered using 1 mol% of FeCl₃ as catalyst and the reaction also proceeded very rapidly in an ionic liquid. We also found that 3～5 mol% of Fe(ClO₄ )₂ ?Al₂ O₃ or Fe(BF₄ )₂ ?6H₂ O-successfully catalyzed Friedel-Crafts type alkylation of indoles or pyrroles with vinyl ketones or α-aryl-β-silylalcohol. In particular, the reaction of chiral α-aryl-β-silylalcohol with indole using Fe(ClO₄ )₃ ?nH₂ O as catalyst proceeded with retention of the configuration of stereochemistry of the hydroxyl group. Then, we discovered the first example of iron-catalyzed enantioselective C-S bond formation via Michael addition of thiols to (E)-3-crotonoyloxazolidin-2-one using 10 mol% of Fe(BF₄ )₂ /Pybox. We further demonstrated that Fe(ClO₄ )₃ ?Al₂ O₃ -catalyzed the Nazarov type cyclizations of thiophene, pyrrole, indole, benzofuran, and benzo[b]thiophene derivatives using ionic liquids as solvent. Solvents have been recognized as a by-player in chemical reactions in the process of "optimization of reaction conditions". However, further investigation of the solvent-driven iron-catalyzed reaction will allow discovery of useful reactions for organic syntheses.

Full text of DOI:10.3987/REV-16-842

HETEROCYCLES, Vol. 92, No. 8, 2016, pp. -. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 18th March, 2016, Accepted, 19th April, 2016, Published online, 3rd June, 2016
DOI: 10.3987/REV-16-842
DEVELOPMENT
REACTIONS
OF
SOLVENT-DRIVEN
IRON-CATALYZED
Toshiyuki Itoh
Department of Chemistry and Biotechnology, Graduate School of Engineering,
Center for Research on Green Sustainable Chemistry, Tottori University, 4-101
Koyama-minami, Tottori 680-8552, Japan
Abstract – The possibility of solvent-driven iron-catalyzed reactions has been
investigated using ionic liquids and acetonitrile as key solvents. Three
iron-catalyzed reactions, the intramolecular cyclization of cyclopropane
dithioacetals, the [2+2]-cycloaddition of (trans)-anethole, and the [2+3]-type
cycloaddition of styrene derivatives with 1,4-benzoquinone, were first developed
using acetonitrile as solvent in the presence of 3~5 mol% of Fe(ClO4)3•Al2O3 or
Fe(BF4)2•6H2O under air conditions. In particular, we found the rapid
cycloaddition of iron-catalyzed [2+3]-type cycloaddition of styrene derivatives
with 1,4-benzoquinone when the reaction was carried out in an ionic liquid which
contained [PF6] or [Tf2N] anion. Homo-coupling reaction of aryl or alkynyl
Grignard reagent was next discovered using 1 mol% of FeCl3 as catalyst and the
reaction also proceeded very rapidly in an ionic liquid. We also found that 3~5
mol% of Fe(ClO4)2•Al2O3 or Fe(BF4)2•6H2O-successfully catalyzed Friedel-Crafts
type alkylation of indoles or pyrroleswith vinyl ketones or α-aryl-β-silylalcohol.
In particular, the reaction of chiral α-aryl-β-silylalcohol with indole using
Fe(ClO4)3•nH2O as catalyst proceeded with retention of the configuration of
stereochemistry of the hydroxyl group. Then, we discovered the first example of
iron-catalyzed enantioselective C-S bond formation via Michael addition of thiols
to (E)-3-crotonoyloxazolidin-2-one using 10 mol% of Fe(BF4)2/Pybox. We further
demonstrated that Fe(ClO4)3•Al2O3-catalyzed the Nazarov type cyclizations of
thiophene, pyrrole, indole, benzofuran, and benzo[b]thiophene derivatives using
ionic liquids as solvent. Solvents have been recognized as a by-player in chemical
reactions in the process of “optimization of reaction conditions”. However, further
investigation of the solvent-driven iron-catalyzed reaction will allow discovery of
useful reactions for organic syntheses.

1. INTRODUCTION
Iron is one of the most abundant and environmentally friendly metals on the earth and there have been
various types of iron metal-catalyzed organic transformations during the past decades.1 Solvents provide a
favorable environment for the intermediates of the chemical reaction and enhances the reactivity of the
catalysts. However, solvents have been recognized as a by-player in chemical reactions in the process of
“optimization of reaction conditions”. We have been investigating the possibility of iron-catalyzed
reactions by focusing on the solvent not as a supporting actor of the reaction but as an educator that
brings out a masked ability of the iron cation: we have thus developed several of them, i.e., the
intramolecular cyclization of cyclopropane dithioacetals,2 the [2+2]-cycloaddition of (trans)-anethole,3
the [2+3]-type cycloaddition of styrene derivatives with 1,4-benzoquinone,4 the Michael addition of
β-ketoesters to vinyl ketones,5 the enantioselective Michael addition of thiols to unsaturated carbonyl
compounds,6 Friedel–Crafts type alkylation of indoles or pyrroles with vinyl ketones7 or
α-aryl-β-silylalcohol,8 homo-coupling reaction of aryl or alkynyl Grignard reagent,9 and the Nazarov type
cyclization of thiophene,10,11 pyrrole,12,13 indole,14 benzofuran,14and benzo[b]thiophene derivatives.14 In
this chronicle, I report the story of how we developed these iron salt-catalyzed reactions from the
beginning to the most recent ones.
2. IRON-CATALYZED REACTIONS BEGAN FROM A SINGLE ELECTRON OXIDATION
Kratochvil and Long reported that the reduction potential of the iron(III)-(II) couple depended on the
solvent system which was estimated to be 1.57 volts in acetonitrile (MeCN).15 I was strongly fascinated
by the results because “1.57 volts” was a sufficient level for the single electron oxidation of organic
molecules. On the contrary, the oxidation potential of a Fe3+ ion shown in textbooks of Inorganic
Chemistry was 0.77 volt which was slightly insufficient to oxidize common organic molecules to
generate cation radical species. Inspired by the results, I had decided to launch the present project of
“development of a solvent driven iron-catalyzed reaction” in 1998. It was by sheer chance for me that I
read the article of Kratochvil and Long: an abstract of the paper was in a neighboring column on a page of
Chemical Abstracts when I looked for papers concerning the oxidation level of various metal cations as I
prepared a lecture in graduate school. We had a strong interest in the iron(III)-catalyzed reactions
emanating from a single electron oxidation in MeCN or an ionic liquid (IL) solvent system. ILs have now
attracted great interest because of their characteristics of low-volatility, non-flammability, high ion
conductivity, and a wide potential window;16 however, they were not popular in those days. In fact, there
were neither commercially available ILs nor any report referring to the oxidation potential of Fe3+/Fe2+
when we began the project; the answer was reported by Yamagata and Katayama et al. to be 1.1 V in an
ionic liquid, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide ([bmim][Tf2N]) in 2005

(Figure 1).17 We also anticipated that the Lewis acidity of Fe3+ ion might be increased in ILs: because ILs
consisted of non- or less coordinated anions and organic cationic molecules so that iron cation might exist
as a “naked cation” in an IL solvent.
Eo/V= 1.1 V
Fe3+ + e
Eo/V= 1.1~1.5
Fe3+ + e
in
Eo/V= 0.77
Fe3+ + e
Fe2+
Fe2+
Fe2+
MeCN
Bu
Me
N
N
Tf2N-
in
in
H2O
Katayama et al. 17
Figure 1. The reduction potential of the iron(III)-(II) couple in different solvent systems
Since there were no commercially available ILs in those days, we prepared ILs for the solvents of
iron-catalyzed reactions ourselves and also established a method of recycling them.18 This experience
became a valuable asset for our group because we accumulated much important know-how on to use ILs
during the study.
We had started the present project by the investigating a single electron oxidation followed by the
ring-opening reaction of cyclopropanes using MeCN as a solvent, because it was well known that the
cyclopropane ring opened easily to generate a carbon radical.19 Several examples of ring-opening
reactions of the cyclopropane ring had been reported (Figure 2). Booker-Milburn and co-workers reported
that iron(III)-mediated oxidative ring opening of the cyclopropane compound 1 took place and gave the
cyclized product 2 through the intermediate 1#, although the reaction required 3 eq. of iron(III) salts vs.
substrate 1 to complete the reaction (Figure 2, left reaction).20 Takemoto and co-workers reported the
similar reaction using a catalytic amount of an oxidant (0.5 eq. of (p-BrPh)3NSbCl6), and succeeded in
obtaining bicyclopentane 4 from p-tolylthio-substituted cyclopropane 3 through cation radical 3# as
illustrated in the right reaction in Figure 2. 21
Bn
(p-BrPh)3NSbCl6
(0.5 eq.)
X
FeCl3 or Fe(NO3)3
(3 eq.)
H
TMSO
O
Tol
S
Tol
S
Bn
CH2Cl2, 0 °C,
30 min
R
DMF, rt ~ 60 °C
H
1
3
4
2
X= H,
Cl, SPh
-e
+e
OMe
-e
O
Bn
Tol
S
X
+
R
1#
3#
Figure 2. Early examples of cyclization that started from single electron oxidation

Based on the results, we hypothesized that ring-opening of cyclopropanonetrimethylenethioacetal 722
might occur by treatment of iron(III) salt in MeCN as a solvent, because it was reported the reduction
potential of dithioacetal was estimated to be 0.88 volt.23 The desired reaction was indeed realized when 7
was treated with 10 mol% of iron(III) perchlorate (Fe(ClO4)3•nH2O) in MeCN under air, subsequent
cyclization with the olefinic part and reduction by an additional 1,3-dithiane giving cis-fused
oxabicyclo[3.3.0]octane-1,1-trimethylenethioacetals 8 (Figure 3).2 It was revealed that the key solvent
was MeCN and no reaction took place in dichloromethane (CH2Cl2), hexane, toluene, THF, or H2O.2 The
plausible mechanism was suggested by the PM3 calculation illustrated in Figure 3: the single-electron
oxidation of the sulfur atom on 7 to afford the cation radical 7-1# which easily generated 7-2# by the ring
opening reaction and subsequent cyclization to afford 7-3# that formed the final intermediate 7-4#, which
was finally reduced by 1,3-dithiane to give 8.
Fe(ClO4)3•nH2O (10 mol%)
H
S
air
(1.0 eq.)
O
S
S
O
S
S
S
MeCN, rt, 1.5 h
Y= 68%
H
7
8
S
S
Fe3+
Fe2+
O2
O2
S
S
S
S
S
S
S
S
S
S
CH2
H
H
O
O
O
O
7-1#
7-2#
7-3#
7-4#
Figure 3. Iron(III) salt-catalyzed radical cyclization of cyclopropanone dithioacetal in MeCN
We next found [2+2] cyclodimerization of (trans)-anethole (9) and synthesized cyclobutane 10 in 92%
yield with perfect anti-selectivity in the presence of 3 mol% of iron(III) salts (Figure 4):3 iron
(III)perchlorate (Fe(ClO4)3•Al2O3) catalyzed the reaction and anti-adduct 10 was produced as the sole
product due to the presence of equilibrium of the final intermediate syn-10# and anti-10#.

OMe
MeO
Fe(ClO4)3•Al2O3
(3 mol% )
MeO
MeCN, rt, 66 h
Y= 92%
Me
Me
Me
10
9
Fe3+
Fe2+
Fe3+
Fe2+
Ar
Ar
Ar
Me
Me
anti-10#
Me
Me
Ar
9#
Ar= 4-MeO-C6H4-
Ar
Ar
Me
Me
syn-10#
Figure 4. Iron(III)-catalyzed cyclodimerization of (trans)-anethole
Based on these results, we next tested reaction of (trans)-anethole with but-3-en-2-one (11). Although the
desired [2+2]-cycloaddition product 12 was indeed obtained, we failed to improve the chemical yield
(Figure 5). Hence, we switched the reactant to 1,4-benzoquinone 13 from 11, and found that the product
was not the expected [2+2]-cycloadduct 14 but 2,3-dihydrobenzofuran derivative 15 with excellent yield
(92%) in the presence of just 3 mol% of Fe(ClO4)3•Al2O3 in MeCN as solvent.4a On the other hand,
Engler and co-workers reported the preparation of the same compound using 1.2 eq. of Ti(IV) salt (TiCl4:
Ti(OiPr)4 = 1.8:1) in 68% yield.24
O
O
13
Fe(ClO4)3 •Al2O3
(3 mol%)
MeO
O
MeO
OH
MeCN
Me
Me
9
15
O
Y= 93% (13:1)
O
O
Me
11
[2+2]
13
Fe(ClO4)3 •Al2O3
(10 mol%)
O
MeO
O
MeO
O
Me
Me
14
Me
12
Y= 39%
Figure 5. Reaction of (trans)-anethole with electron defficient olefinic compounds in the presence of
iron(III) salt

We obtained very important results for further investigation in this study: the reaction rate drastically
accelerated when the reaction was carried out in ILs as solvents (Scheme 1 and Table 1). To our surprise,
the reaction was completed in less than 10 min in 1-butyl-3-methylimidazolium hexafluorophosphate
([bmim][PF6]), while it took 2 hours in MeCN with the same concentration (entries 1 and 2 in Table 1).
MeO
cat. Fe3+
O
MeO
9
Me
OH
solvent, rt
under air
Me
O
O
15
13
Scheme 1
Table 1. Iron-catalyzed [2+3]-cyclization of (trans)-anethole with benzoquinone
Entry Solvent
Cat. (3 mol%)
Yield of 15
(trans/cis)
93% (13:1)
90% (15:1)
91% (11:1)
94% (12:1)
no reaction
98% (11:1)
no reaction
68% (43:1)
98% (15:1)
no reaction
no reaction
63% (25:1)
93% (15:1)
1
MeCN (rt 2 h)
Fe(ClO4)3•Al2O3
Fe(ClO4)3•Al2O3
FeCl3
2
[bmim][PF6] (rt 10 min)
[bmim][PF6] (rt 10 min)
[bmim][PF6] (rt 4 h)
3
4
FeCl2
5
[bmim][PF6] (rt 24 h)
[bmim][PF6] (rt 10 min)
MeCN (rt 24 h)
FeSO4•7H2O
Fe(BF4)2•6H2O
Fe(BF4)2•6H2O
Fe(BF4)2•6H2O
Fe(BF4)2•6H2O
Fe(BF4)2•6H2O
Fe(BF4)2•6H2O
Fe(BF4)2•6H2O
Fe(BF4)2•6H2O
6
7
8
[bmim][BF4] (rt 3 h)
9
[bmim][Tf2N] (rt 10 min)
[bmim][OTf] (rt 24 h)
[bmim][n-C5H11SO4] (rt 12 h)
[N221ME][BF4](rt 2 h)
10
11
12
13
[N221ME][Tf2N] (rt 10 min)
It was found that even iron(II) dichloride (FeCl2) worked as a good catalyst in the IL (entry 4), though a
long period was required to complete the reaction. On the contrary, no product was obtained for iron(II)
sulfate (FeSO4) (entry 5). We finally found that iron(II) tetrafluoroborate (Fe(BF4)2•6H2O) worked the
best in [bmim][PF6] as a solvent (entry 6). Since the reaction proceeded smoothly under dry air conditions
and it was well known that ferrous ion was easily oxidized by air to generate ferric ion, the real catalyst
was speculated to be Fe3+ cation which caused the initial oxidation of (trans)-anethole (9). However,

since Fe(BF4)2•6H2O provided no product in MeCN (entry 7), the reactivity of this salt was strongly
dependent on the solvent system. We further found that the reaction was also influenced by the
counter-anion of the ILs employed as solvent. Very rapid reaction was also recorded for [bmim][Tf2N]
(entry 9), while the reaction rate was dropped for [bmim][BF4] (entry 8), and no reaction occurred when
[bmim][OTf] or [bmim][n-C5H11SO4] was used as solvent (entries 10 and 11). Rapid reaction was again
observed in N,N-diethyl-N-methyl-N-(2-methoxy)ethylammonium bis(trifluoromethylsulfonyl)amide
([N221ME][Tf2N]) (entry 13), and the reaction rate declined for [N221MEM][BF4] (entry 12). It was thus
found that the reaction rate depended on the anions of the ILs in the following order, PF6≃Tf2N>>BF4.
These results indicated that the counter-anions of both the iron cation and the ILs might play the key role
in realizing this [2+3]-cycloaddition.
Engler et al. proposed that 2,3-dihydrobenzofuran 15 was generated by [2+2]-cyclization of anethole 9
with benzoquinone 13 and subsequent rearrangement of the resulting cation intermediate.24 The reaction
was stopped by addition of 1 eq. of TEMPO, then the positive solvatochromism was observed when the
reaction was conducted in [N221ME][Tf2N]; these results indicated that a radical cation or anion
intermediate existed in the reaction course.4c ILs are highly polar liquids, hence the environment provided
by the IL might be appropriate for generation of a radical cation intermediate but not stabilize it because
[PF6] or [Tf2N] anion is a less coordinative anion. Therefore, marked acceleration was accomplished.
Fuchigami and co-workers reported that a charge-separated intermediate was destabilized by an IL and
accelerated the corresponding reaction.25 Another mechanism might also be possible: the “naked Fe3+
cation” may coordinate with 1,4-benzoquinone 13 and accelerate electron transfer reaction to
(trans)-anethole (9). Although we were the first to find the activation of the iron salts mediated reaction
by ILs, we did not pursue this further. Lee, Song and co-workers reported many examples of activation of
several Lewis acids using ILs three years later after our publication; the activity of a Lewis acid depended
on the counter anions of the solvent ILs following the order PF6>Tf2N>>BF4.26,27,28 This was almost the
same as that we obtained in the reaction of iron-catalyzed [2+3]-cyclization of (trans)-anethole with
benzoquinone in ILs.
Styrene derivative 16 reacted with benzoquinone 13 in the presence of Fe(ClO4)3•Al2O3 in MeCN gave
the adduct 17 in 84% yield. Then, the acetyl group of 17 was removed by methanolysis to afford 18
which was converted to optically active acetate 19 with >99% ee via lipase-catalyzed transesterification
as shown in Figure 6.4b The aim to catalyze the reaction of acetate 16, Fe(ClO4)3•Al2O3/ MeCN resulted
better results as a catalyst than that of Fe(BF4)2•6H2O/[bmim][PF6].

MeO
Fe(ClO4)3 •Al2O3
(3 mol%)
16
K2CO3
O
O
MeO
MeO
OAc
OH
OR
O
MeOH
quant.
MeCN, rt, 2 h
Y= 84%
17
OAc
OH
18
O
13
18
Novozyme
O
O
R= H, E= 10
R= Me, E= 49
R= Bn, E >200
O
MeO
OR
i-Pr2O, 35 °C
R= MOM, E= 100
OAc
19
>99% ee
Figure 6. Preparation of chiral 2,3-dihydrobenzofuran derivatives by a combination of iron(III)-catalyzed
cycloaddition reaction and subsequent lipase-catalyzed transesterification. “E value”29 indcates the
enantioselectivity of this enzymatic reaction: E= ln(1-c)(1+ ee19)/ln(1-c)(1-ee19)], here c means conv.
which was calculated by the following formula: c= ee18/(ee19 + ee18). For details see ref. 29
This work revealed an interesting property of ILs in activating of electron transfer type reactions. Since
electron transfer is the essential starting point of many chemical reactions, we next focused on the
possibility of ILs-driven iron-catalyzed reactions.
Recently iron-catalyzed cross coupling reactions have gained strong interest among synthetic chemists.30
Among such examples, we turned our attention to the FeCl3-mediated homocoupling reaction of aryl
Grignard reaction reported by Hayashi31 and Cahiez et al.32 The authors proposed that the reaction
included electron transfer steps and the key step might be a reduction step of iron (III) cation by aryl
Grignard reagent or a transmetallation step on the iron.31a However, ILs have been considered
inappropriate for strong base-mediated reactions. Clyburn and co-workers reported the first example of
Grignard reaction in an IL.33 Since then, several groups, including ours, reported successful examples of
the designs ILs for strong base-mediated reactions such as the Grignard reaction.34-36 We succeeded in
designing an IL by introduction of alkyl ether moiety on the side arm of phosphonium salt:
methoxyethyl(tri-n-butyl)phosphonium bis(trifluoromethanesulfonyl)imide ([P444ME][NTf2]) was thus
developed.36 We applied this IL as solvent of the homo-coupling reaction of aryl Grignard reagent in the
presence of 1 mol% of FeCl3 using 1,2-dichloroethane or 1,2-diiodoethane as an oxidant (Figure 7).9
We found that the desired coupling reaction of 20 proceeded very rapidly; 21 was obtained in less than 5
min at 0 °C in excellent yields (86 ~ 100%) except for bulky 2,4,6-tirimethylphenylMgBr.9 The reaction
using 2-thienylMgBr 22 was very successful and the desired bithiophene 23 was obtained in 91% yield
after just 10 min reaction at 25 °C. The IL solvent system was also useful for the homo coupling reaction

of alkynyl Grignard reagent.9 In this case, use of 1,2-diiodoethene was essential to afford the coupling
product, and we obtained the desired 25 in 80% yield.9
FeCl3 (1 mol%)
ClCH2CH2C l(DCE)
R
MgBr
(1.2 eq.)
R
R
IL-THF (5:1), 0 °C, 5 min
20
21
R= o- or p-OMe, Me
Y= 86~ 100%
S
MgBr
S
S
IL-THF (5:1), 25 °C, 10 min
22
24
23
Y= 91%
FeCl3 (1 mol%)
ICH2CH2I (DIE)
(1.2 eq.)
F3C
CF3
F3C
MgBr
IL:
IL-THF (2:1), 0 °C
25
Y= 80%
Bu
Tf2N
Bu
Bu
P
OMe
[P444ME][NTf2]
Figure 7. Iron(III)-catalyzed homo-coupling reaction of aryl or alkynyl Grignard reagents
3. IRON-CATALYZED FRIEDEL–CRAFTS TYPE ALKYLATION IN AN IL SOLVENT
SYSTEM
We next investigated iron-catalyzed Friedel–Crafts type alkylation in ILs, focusing in particular, on the
use of indole7a,7c and pyrrole7b derivatives as donor molecules, because the products of the reactions
contain important structural motifs found in natural products and are essential intermediates in the
preparation of pharmaceuticals and other chemicals.
The Lewis acid-mediated Friedel Crafts type alkylation of indole with unsaturated carbonyl compounds
has gained growing interest.37 However, due to the basicity of indole, protection of the nitrogen atom in
the indole ring was essential to realize such alkylation.37 In the previous chapter, we found that
Fe(ClO4)3•Al2O3 and Fe(BF4)2•6H2O worked as excellent catalysts of cycloaddition reaction. We
anticipated that these iron salts might work as an effective catalyst for Friedel–Crafts type alkylation of
the N-protecting group free indole. We found that the reaction indeed proceeded smoothly in MeCN or
ILs as solvent, while no reaction took place when the reaction was conducted in CH2Cl2, MeCl, Et2O,
THF, toluene, or benzene in the presence of 3 mol% of Fe(BF4)2•6H2O under air conditions at rt.7 We thus
obtained 27a in 92% yield when indole 26 (R= H) was reacted with 5-phenylpent-1-en-3-one (Figure 8).7a

The reaction of indole with cyclopentenone afforded 27b in 86% yield.7a Unfortunately, the reaction in
the presence of chiral ligands, such as the (R,R)-Jacobsen38 or (S,S)-bis-(oxazolinyl)pyridine (pybox)
ligand,39 gave the product with a racemic state under our reaction conditions, 7a although Xia and Huang
et al. recently reported chiral Brφnsted acid directed FeCl3-catalyzed enantioselective alkylation of
indol.40
Control of regioselectivity of electrophilic substitution reaction of indole is an important task to be solved.
We expected that regioselective electrophilic alkylation might be obtained using weak Lewis acid
Fe(BF4)2•6H2O or Fe(ClO4)3•Al2O3 as a catalyst. As expected, the reaction showed perfect
regioselectivity: alkylation took place at 3-position of the indole 26 to give 3-alkylated product 27: we
thus succeeded in obtaining the indole derivatives 27a and 27b were obtained in 92% and 86%,
respectively (Figure 8, upper).7c We further established that the second alkylation took place at 2-position
of 27. After optimization of the reaction conditions, interestingly, solvent free conditions gave the best
results: 7-methylindole 26c was reacted with hept-1-en-3-one in the presence of 3 mol% of
Fe(ClO4)3•nH2O to form 3-alkylated compound 27c, after completion the reaction, addition of
non-1-en-3-one with additional 5 mol% of Fe(ClO4)3•nH2O afforded the desired 2,3-double alkylated
indole 28 (Figure 8, down).7c In the case, it was supposed that substrate indole and vinyl ketone worked as
good solvents for the iron-catalyzed reactions.
O
O
or
(1.2 eq.)
(1.2 eq.)
R1
Fe(BF4)2•6H2O
(3 mol%)
O
O
Ph
or
N
H
N
H
[bmim][Tf2N], rt, under air
N
H
26
27a (Y= 92%)
27b (Y= 86%)
O
O
(1.2 eq.)
(1.2 eq.)
R1
Fe(ClO4)3•nH2O
(3 mol%)
R2
O
O
R1
R2
+ Fe(ClO4)3•nH2O
(5 mol%)
R1
N
H
N
60 °C, 20 min
solvent free
N
H
Me
40 °C, 5 h
H
O
Me
Me
solvent free
26c
27c
28 Y= 70%
R1= n-Bu, R2= n-hex
Figure 8. Iron salt-catalyzed alkylation of indole derivatives
The pyrrole group is found in many natural products as an important structural motif. However, since
pyrrole is very sensitive to strong Lewis or Brφnsted acid, no electrophilic alkylation method had been
reported when we launched the project. Although we tested the reaction of pyrrole with 1-buten-3-one in

the presence of 3 mol% of FeCl3, neither alkylated product nor starting compound and only polymerized
compounds were formed.7b We found that 2,5-dialkylated pyrrole and 2,3,5-trialkylated pyrrole was
obtained in 37% and 12% yield, respectively, when the reaction was carried out in the presence of 3
mol% of Fe(BF4)2•6H2O in MeCN.7b After optimization of the reaction conditions of 2-acetylpyrrole 29,
we established double alkylation of 2-acetylpyrrole with vinyl ketones using 3 mol% of Fe(ClO4)3•Al2O3
and succeeded in preparing tri-substituted pyrrole derivative 30a, 30b, and 30c in an 80%, 52%, and 78%
yield, respectively (Figure 9).7b Solvent free conditions again gave the best results, though the reaction
itself proceeded very smoothly in an IL, [bmim][Tf2N], because extraction of the products from the IL
layer was unsuccessful using conventional organic solvents such as ether, cyclohexane, ethyl acetate or
CH2Cl2.
O
R
H
N
O
O
Fe(ClO4)3•Al2O3
(3 mol %)
O
H
N
R
R
neat, 60 °C
O
29
30a: R= Me, Y= 80%
30b: R= CH2SPh, Y= 52%
30c: R= n-C5H11, Y= 78%
Figure 9. Iron-catalyzed alkylation of 2-acetytlpyrrole with vinyl ketones
We next turned our interest to the Friedel–Crafts alkylation using α-aryl alcohols as alkylating agents,41
because several leading works had been reported.42 We found that the cationic iron salt Fe(BF4)2•6H2O
was a very effective catalyst for the Friedel–Crafts alkylation of indole derivatives 31 with β-silyl-
alcohols 32. The combination of indole derivatives with 2-furyl and 2-thienyl derivatives using
Fe(BF4)2•6H2O was the best system and the corresponding products 33a to 33d were obtained in high
yield; on the other hand, Fe(ClO4)3•nH2O gave better results for the reaction of phenyl derivative of
β-silylalcohol, and 33h was obtained in good yield (Figure 10).8 However, no reaction took place for the
reaction of 5-cyano- or nitro-1H-indole. In addition, reaction of indole with
1-(pyridin-2-yl)-2-(trimethylsilyl)ethanol also gave no desired product (Figure 10).

Fe(ClO4)3•nH2O
(5 mol%)
Fe(BF4)2•6H2O
(5 mol%)
R2
or
OH
SiMe3
SiMe3
+
R2
R1
31
N
H
R1
neat, 40 °C, 24 h
N
32
H
33
S
O
O
O
Br
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
N
H
N
H
N
H
N
H
N
H
Me
33d
33e
33a
33c
33b
Y= 96%
Y= 70%
Y= 96%
Y= 73%
Y= 91%
F
CF3
OMe
NC
O2N
N
H
SiMe3
N
SiMe3
SiMe3
H
N.R.
N.R.
N
H
N
H
N
H
OH
SiMe3
N
33h
33g
33f
Y= 76%
Y= 54%
N.R.
Y= 70%
Figure 10. Iron salt-catalyzed Friedel–Crafts type alkylation of indole derivatives with β-silylalcohols
During the course of this study, we discovered that the Friedel–Crafts alkylation of chiral α-arylalcohols
with a trimethylsilyl group was found to proceed with retention of the configuration of the hydroxy group
as a leaving group (Figure 11).8 Although the memory of chirality is useful in carbanion chemistry,43 such
reaction in carbocation chemistry is rare and there is no general means of achieving it.44 Ugi and
co-workers first reported the retentive electrophilic substitution of the α-substituted alkylferrocenes.45
Another example is the electrochemical generation of the N-acyliminium ion and the in situ trap with a
nucleophile reported by Matsumura and Onomura et al.46 To our surprise, chiral alkylation product
(+)-(R)-33e (91% ee) was obtained when we subjected chiral β-silylalcohol (+)-(S)-32e (92% ee) to the
reaction of indole 31a (Figure 11).8 The result indicated that the Friedel–Crafts alkylation of chiral
β-silylalcohols proceeded with retention of the configuration. After optimization of the catalyst, we found
that the same level of the memory chirality reaction was observed with other Lewis acids such as AlCl3,
FeCl3, and Sc(OTf)3, but it was confirmed that our iron catalyst was most effective to realize the reaction.
The stereoselective reactions of carbocations have gained strong interest among synthetic chemists.47
Bach and co-workers reported syn-selective Friedel–Crafts alkylation at the benzylic position of
2,3,3-trimethyl-1-phenylbutan-1-ol using 1.2 molar equivalent of strong Lewis or Brφnsted acid through
benzylic carbocation intermediate,48 and they also reported successful diastereoselective reactions via
carbocation intermediates.48 But this reaction, however, is the diastereoselective reaction but the memory

chirality reaction: we are now assuming that the origin of the reaction stems from the carbocation
intermediate which is conformationally stable.8
Me
Me
Me
Si
Si
Fe(ClO4)3·nH2O
(5 mol%)
Me
H
H
+
Me
Me
(R)
HO
N
H
(S)
neat, 40 °C, 24 h
Y=67%
N
H
(R)-33e
(S)-32e
31a
92% ee
91% ee
(R)-33e
Figure 11. Friedel–Crafts type alkylation of indole with chiral β-silylalcohol
4. IRON-CATALYZED CONJUGATED REACTION
Conjugate addition is one of the most important bond forming reactions in synthetic organic chemistry.
The asymmetric conjugate addition of thiols to α,β−unsaturated substrates is also a very useful reaction
because it produces optically active compounds such as pharmaceuticals.49 The first example was reported
by Kanemasa et al. in 1999: Ni/DBFOX catalyzed the highly enantioselective reactions.50 However, there
have been only limited examples of the transition metal catalyzed enantioselective addition of thiols to
(E)-3-crotonoyloxazolidin-2-one. We found the chiral cobalt or iron catalyzed asymmetric conjugate
addition of aromatic thiols (34) to (E)-3-crotonoyloxazolidin-2-one (35) (Figure 12).6 Several types of
thiols were reacted with (E)-3-crotonoyloxazolidin-2-one to provide the desired chiral adducts with high
optical purities (Figure 12).6 Aiming at obtaining high enantioselectivity, the reaction was conducted at a
lower temperature (–20 ˚C) in the presence of molecular sieves 4Å and we thus succeeded in obtaining
the addition products, 37a ~ 37e with high optical purity. The highest enantioselectivity (95% ee) was
recorded for the reaction of the sterically hindered 2-methylbenzenethiol (37d), though it required a
longer time to complete the reaction (Figure 12).6b

Fe(BF4)2 (10 mol%)
RSH
34
SR
O
O
L1 (10 mol%)
Me
N
O
O
O
THF, MS 4A, -20 °C
37
Me
N
O
R= Ph, 90% ee (Y=93%)
(-20 °C, 72 h)
O
35
O
X
N
N
L1: X= N, R= iPr {(S,S)-ip-Pybox}
Cl
Cl
Me
S
O
O
S
O
O
S
O
O
N
S
O
O
S
O
O
Me
N
O
Me
N
O
Me
O
Me
N
O
Me
N
O
37e
37c
37d
37a
37b
91% ee (Y=72%)
(-20 °C, 168 h)
95% ee (Y=92%)
(-20 °C, 108 h)
85% ee (Y=84%)
(-20 °C, 24 h)
89% ee (Y=96%)
(-20 °C, 72 h)
87% ee (Y=99%)
(-20 °C, 24 h)
Figure 12. Enantioselective C-S bond formation by iron/Pybox catalyzed Michael addition of thiols to
(E)-3-crotonoyloxazolidin-2-one
The 1,4-addition of appropriate donor molecules such as active methylene compounds with
α,β-unsaturated carbonyl compounds is well recognized as an important C-C bond forming reaction in
organic synthesis.51 Transition-metal catalysis of the 1,4-additions have recently been developed as a
valuable alternative to the classic base catalyzed reaction.51 We found that the 1,4-addition reaction of
β-ketoester 38 with vinyl ketones was accomplished by Fe(BF4)2•6H2O as catalyst to afford desired
product 39a ~ 39c in modest (45%) to excellent (93%) yield, and the catalyst was used repeatedly more
than 10 times in an ionic liquid solvent system (Figure 13).5
O
R
O
O
O
Fe(BF4)2·6H2O (3 mol%)
CO2Et
R
CO2Et
OMe
Tf2N
Et
Et
N
38
39
Me
39a: R= Me, Y= 93%
39b: R= n-C5H11, Y= 86%
39c: R= Ph, Y= 45%
rt, 0.5 h + air
Figure 13. Iron-catalyzed 1,4-addition reaction of β-ketoester with vinyl ketone
To gain the insight of the reaction mechanism in the present reaction, we tested the additive effect of
2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO). Interestingly, the inhibitory action of

TEMPO was significantly dependent on the reaction medium. The reaction was completely inhibited by
TEMPO with an equal amount of the catalyst (3 mol%) in MeCN. On the other hand, 1.0 eq. of TEMPO
was needed to inhibit the reaction in the ionic liquid solvent. These results may indicate that the catalytic
mode of Fe(BF4)2 depends on the solvent system. Although we attempted to isolate TEMPO-iron complex,
we isolated neither TEMPO-substrate complex nor TEMPO-Fe salt complex from the reaction mixture.5
5. IRON-CATALYZED NAZAROV CYCLIZATION
Nazarov cyclization is promoted by Lewis or Brφnsted acids and is known as an important method for the
preparation of five-membered carbocycles.52 Iron(III) chloride (FeCl3) is well recognized as the most
typical strong Lewis acid and Denmark and Jones reported the first example of the FeCl3-catalyzed
Nazarov cyclization;53 Kang and co-workers extended the catalytic reaction.54 Initially, we gave our
attention to the use of FeCl3 for the Nazarov cyclization of the 3-substituted thiophene derivative 40,
because thiophenes are respected as important components of many biologically active compounds and
some optical materials. We established that the combination of FeCl3 (10 mol%) with toluene as a solvent
was the best system to afford the desired product when the reaction was carried out at 60 °C (Figure 14).10
The reaction of substrate which has an electron donating group, such as the phenyl, p-tolyl, or
p-methoxyphenyl group proceeded smoothly and gave the cyclized products 41a, 41b, and 41c in 90%,
82% and 83%, respectively. On the other hand, the reaction rates of substrates that have an electron
withdrawing group or aliphatic group, such as p-cyanophenyl or cyclohexyl group, were significantly
lower and 41d and 41e were obtained in 52% and 47% yield, respectively (Figure 14).10
O
O
R
O
O
FeCl3 (10 mol%)
toluene, 60 ˚C
OR'
OMe
S
S
R
40
41
O
O
O
O
O
O
O
O
O
O
OMe
OMe
OMe
OMe
OMe
S
S
S
S
S
CN
41d, Y= 52%
OMe
41c, Y= 83%
Me
41a, Y= 90%
41b, Y= 82%
41e, Y= 47%
Figure 14. FeCl3-catalyzed Nazarov cyclization of thiophene derivatives
We next found that the cyclized product 43a was obtained when substrate 42 (Ar= Ph) was heated at
60 °C in the presence of 20 mol% of Fe(OTf)2 with (S,S)-tb-pybox (L2) in a mixed solvent of

CH2Cl2-hexane (2:1) with 83% ee.11 The enantioselectivity was increased when 42b (Ar= 4-CF3-C6H4)
was subjected to the reaction using Fe(OTf)2/L to give 43b in 53% yield with 89% ee (Figure 15). The
best enantioselectivity was recorded for 42c (Ar= 2-naphthyl) and 43c was obtained in 40% yield with
93% ee (Figure 15).11 This example was the first iron-catalyzed asymmetric Nazarov cyclization.
O
O
N
Fe(ClO4)2•6H2O / Ligand
(20 mol%)
N
N
L2
O
O
O
O
or
L2 ((S,S)-tb-pybox)
Fe(OTf)2/Ligand
OEt
OEt
Ar
Ar
CH2Cl2 or toluene , 60 °C
42
43
43a: Ar= Ph, Y= 69% (83% ee)/ CH2Cl2-hexane (2:1)
43b: Ar= 4-CF3-C6H4, Y= 53% (89% ee)/ toluene
43c: Ar= 2-Naphthyl, Y= 40% (93% ee)/ toluene
Figure 15. Iron-catalyzed asymmetric Nazarov cyclization
The pyrrole moiety is common in many biologically-active or functional molecules. Therefore, we next
focused on the iron salts-catalyzed Nazarov cyclization of pyrrole derivatives. We anticipated that the key
point to realize the desired Nazarov cyclization might be use of a weaker Lewis acid as mentioned earlier.
It was also assumed that the intermediate of Nazarov cyclization might be favorable in a highly polar IL
solvent. Therefore, we tested the reaction using various combination of iron salts with solvents using
pyrrole derivative 44 as a model substrate. The results were dependent on the combinations of iron salt
with solvent but independent of the stereochemistry of the starting substrate: the desired cyclized product
45 was obtained in excellent yield from (E)-44 and (Z)-44 in 92% yield and 90% yield, respectively,
when the reaction was conducted in the presence of 5 mol% of Fe(ClO4)3•Al2O3 in CH2Cl2 at 60 °C
(Figure 16).12
O
O
O
O
O
O
H
N
Fe(ClO4)3•Al2O3
(5 mol%)
H
N
HN
OMe
OMe
OMe
or
CH2Cl2, 60 °C
45
(E)-44
(Z)-44
Y= 92% from (E)-44
Y= 90% from (Z)-44
Figure 16. Iron salt-catalyzed Nazarov cyclization of pyrrole derivatives

An X-Ray crystallographic analysis of the cyclized product 45 revealed the trans relationship between the
α-carbomethoxy group and the β-phenyl group.12 The solvent choice was very important in the reaction
and CH2Cl2 or the ionic liquids, 1-butyl-3-methylimidazolium bis(trifuluoromethyl)sulfonylamide
([bmim][NTf2]),
([P444ME][NTf2]),
tributyl(2-methoxyethyl)phosphonium
bis(trifuluoromethyl)sulfonylamide
or N,N-diethyl-N-(2-methoxyethyl)-N-methylammonium
bis(trifuluoromethyl)sulfonylamide ([N221ME][NTf2]) provided excellent results.12 Since avoiding the use of
a haloalkane solvent is now a strong requirement from an environmental aspect, this feature is a very
important element in our reaction.
As mentioned earlier, iron-catalyzed 1,4-addition reaction of β-ketoester with vinyl ketone was possible.
In fact, we found that the compound 45 further reacted with but-3-en-2-one to afford the corresponding
Michael product 46a with an excellent trans selectivity in 86~90% yield (Figure 17).12,13 Hence, we next
attempted tandem type Nazarov cylization and 1,4-addition; the yield of desired 46a was only 32% due to
formation of further alkylated compounds on the pyrrole moiety. Desired 46a (R1= Me) and 46b (R1= H)
was obtained in 86% and 87% yield, respectively, when the reaction was conducted as a step-by-step
method (Figure 17).
O
O
O
O
O
Fe(ClO4)3•Al2O3
(5 mol%),
OMe
O
HN
HN
OMe
Me
Me
CH2Cl2 , 0 °C
45
46a
Y= 86% ~ 90%
O
O
O
O
H
N
Fe(ClO4)3•Al2O3
(5 mol%),
O
OMe
O
HN
OR
R1
R1
40 °C
45
CH2Cl2, 60 °C
46a: R1= Me, Y= 86%
46b: R1= H, Y= 87%
44
O
O
O
O
O
[bmim][Tf2N]
60 °C
H
N
OR
HN
OR
Me
Me
O
60 °C
46c: R= n-C5H11
run1 = 78%
run5 = 66%
Figure 17. Iron salt-catalyzed Michael cyclization of pyrrole derivatives; sequential type one pot Nazarov
cyclization/Michael reaction of pyrrole derivatives in an ionic liquid, [bmim][NTf2]

We then investigated the possibility of recycling the iron catalyst for the Nazarov cyclization/Michael
reaction using an ionic liquid, [bmim][Tf2N] as solvent. We initially encountered an unexpected
difficulty; isolation of the product 46a (R= Me) from the reaction mixture was unsuccessful because 46a
was very soluble in [bmim][NTf2]. We finally resolved this by modification of the substrate and using the
n-pentyl ester or benzyl ester instead of the methyl ester. Extraction of the n-pentyl ester 46c from the IL
solvent was successful and we demonstrated repetition of the reaction using [bmim][NTf2] solution as
follows: the reaction course was monitored by silica gel thin layer chromatography analysis and
but-3-en-2-one was added when the spot of 44 had been consumed and the spot of 45 appeared, the
reaction mixture was then stirred at 60 °C until the spot of 45 disappeared completely. The desired
product 46c was isolated as the sole stereo isomer in 78% yield by a mixed solvent (hexane and ether=
2:1). The Nazarov/Michael product 46c was obtained in 66% yield after repetition of the reaction five
times without any addition of the catalyst (Figure 17).13
The Nazarov cyclization of indole, benzofuran, and benzo[b]thiophene was also accomplished in the
presence of catalytic amounts of the iron salts, though we had to choose an appropriate iron salt and
solvent for the substrates. For the indole, the corresponding cyclization product 47 was obtained using
Fe(ClO4)3•Al2O3 in [bmim][Tf2N] in 85% yield. On the other hand, 10 mol% of FeCl3 was essential to
obtain 48 or 49 as catalyst (Figure 18).14 Since the iron catalyst remained in the IL layer, recycling the
catalyst was, of course, possible for the Nazarov cyclization of indole derivatives. We thus succeeded in
obtaining 47 in 79% yield after five repetitions of the reaction without any addition of the catalyst to the
[bmim][NTf2] solvent system.14
O
O
O
O
O
O
H
N
S
O
OR1
OR1
OR1
R
R
R
47
48
49
FeCl3 (10 mol%)
ClCH2CH2Cl, 60 °C,
Y= 52 ~ 64%
R1= Et,FeCl3 (10 mol%),
CH2Cl2, 40 °C, Y= 63%
Fe(ClO3)3•Al2O3 (5 mol%)
[bmim][Tf2N], 60 °C,
Y= 65 ~ 85%
Figure 18. Iron salt-catalyzed Nazarov cyclization of indol, benzofuran, or benzothiophene derivatives
6. CONCLUSION
The most interesting feature of iron is that it can act as various catalyst types for chemical reactions, the
changing of counter anion and solvents. As described in this chronicle, we succeeded in developing many
types of iron-catalyzed reactions (Figure 19). As mentioned in the introduction, the project took from
when I recognized a paper by Kratochvil and Long15 of a reading room in the library of Okayama
University. Since then we have been attempting to expand the scope of iron-catalyzed reaction using ionic

liquids or acetonitrile as key solvents as summarized in Figure 19. Further investigation will allow us to
develop further iron-catalyzed reactions by focusing on the solvent not as a supporting actor of the
reaction but as an educator that brings out a masked ability of the iron cation.
OMe
MeO
H
O
S
S
O
R1
R2
R3
R1
Me
O
Me
H
N
H
O
O
O
OH
R
R
R2
R
Me
Fe2+ Fe3+
O
O
N
H
O
O
OR
R
solvent design
O
Me
Si
Bu
Me
N
N
H
Me
X
MeCN
R
Me
S
O
O
ionic liquids
N
H
Me
N
O
O
O
S
OR
O
R
O
R
R1
OR
O
O
O
O
H
N
R1
OR1
S
O
OR1
O
R2
R2
HN
OR
N
H
O
O
R1
R3
R3
Figure 19. List of compounds developed by the iron-catalyzed reactions in the present study
ACKNOWLEDGEMENTS
The author is most grateful to Dr Hiroyuki Ohara, Professors Eiichi Nakamura (The University of Tokyo)
and Masaharu Nakamura (Kyoto University) for their great contribution to the early studies of the present
project. He is also grateful to Professor Motoi Kawatsura of Nihon University who was an Associate
professor of the author’s group and his great contribution to the Nazarov cyclization project, and also to
Associate Professor Toshiki Nokami of Tottori University for his effort in completing the chirality
retentive Friedel–Crafts alkylation. Finally, the author expresses his deep appreciation to all students (K.
Kudo, H. Kiyokane, K. Kawai, H. Uehara, Y. Komatsu, M. Yamamoto, S. Nomura, K. Ogiso, J.
Kobayashi, S. Matsui, K. Kude, M. Fujiwara, Y. Higuchi, K. Kajita, S. Hayashi, C. Ibara, M. Sakae, M.
Natsuyama, Y. Yamane, and S. Oshitani) who pursued this project with him.
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Toshiyuki Itoh was born in Matsusaka, Mie, Japan, in 1954. He graduated Tokyo University of
Education in 1976. After working as a chemistry teacher in high schools in Mie prefecture, he
decided to go back to the University and received his Ph.D. degree in 1986 from the University
of Tokyo under the supervision of Professor Teruaki Mukaiyama. He was appointed Assistant
Professor of Okayama University in 1987, then promoted to Associate Professor in 1990. He
worked with Professor Anthony G. M. Barrett as a visiting scholar at Colorado State University
in 1990-1991 and moved to Tottori University in 2002, where he was promoted to full
Professor in 2004 and is now director of the Center for Research on Green Sustainable
Chemistry. He is recipient of the Society of Synthetic Organic Chemistry Japan Award (2010),
and The 8th Green and Sustainable Chemistry Award (2009). He served as President of the
Society of Fluorine Chemistry, Japan (2013~2015), and has been the representative of the
managing committee of the Ionic Liquids Research Association, Japan since 2014.