Improving C=N bond reductions with (Cyclopentadienone)iron complexes: Scope and limitations

Article abstract of DOI:10.1002/ejoc.201801348

Herein, we broaden the application scope of (cyclo-pentadienone)iron complexes 1 in C=N bond reduction. The catalytic scope of pre-catalyst 1b, which is more active than the “Kn?lker complex” (1a) and other members of its family, has been expanded to the catalytic transfer hydrogenation (CTH) of a wider range of aldimines and ketimines, either pre-isolated or generated in situ. The kinetics of 1b-promoted CTH of ketimine S1 were assessed, showing a pseudo-first order profile, with TOF = 6.07 h^–1 at 50 % conversion. Moreover, the chiral complex 1c and its analog 1d were employed in the enantioselective reduction of ketimines and reductive amination of ketones, giving fair to good yields and moderate enantioselectivity.

Full text of DOI:10.1002/ejoc.201801348

A Journal of
Accepted Article
Title: Improving C=N Bond Reductions with (Cyclopentadienone)iron
Complexes: Scope and Limitations
Authors: Mattia Cettolin, Xishan Bai, Dennis Lübken, Marco Gatti, Sofia
Vailati Facchini, Umberto Piarulli, Luca Pignataro, and Cesare
Gennari
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801348
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10.1002/ejoc.201801348
European Journal of Organic Chemistry
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Key Topic: Iron Catalysis
Entry for the Table of Contents
FULL PAPER
The catalytic transfer hydrogenation
of imines and the reductive
amination of carbonyl compounds
have been thoroughly investigated
with a cyclooctene-derived
Mattia Cettolin, Xishan Bai, Dennis
Lübken, Marco Gatti, Sofia Vailati
Facchini, Umberto Piarulli,* Luca
Pignataro,* Cesare Gennari*
Page No. – Page No.
(cyclopentadienone)iron pre-catalyst.
Additionally, enantioselective
ketimine reduction with a chiral
(cyclopentadienone)iron complex is
reported here for the first time.
Improving C=N Bond Reductions
with (Cyclopentadienone)iron
Complexes: Scope and Limitations
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10.1002/ejoc.201801348
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Improving C=N Bond Reductions with (Cyclopentadienone)iron
Complexes: Scope and Limitations
Mattia Cettolin,[a] Xishan Bai,[a] Dennis Lübken,[a] Marco Gatti,[a] Sofia Vailati Facchini,[b]
Umberto Piarulli,*[b] Luca Pignataro,*[a] Cesare Gennari*[a]
Abstract: Herein, we broaden the application scope of
(cyclopentadienone)iron complexes 1 in C=N bond reduction.
The catalytic scope of pre-catalyst 1b, which is more active than
the ‘Knölker complex’ (1a) and other members of its family, has
been expanded to the catalytic transfer hydrogenation (CTH) of
a wider range of aldimines and ketimines, either pre-isolated or
generated in situ. The kinetics of 1b-promoted CTH of ketimine
S1 were assessed, showing a pseudo-first order profile, with
TOF = 6.07 h-1 at 50% conversion. Moreover, the chiral complex
1c and its analog 1d were employed in the enantioselective
reduction of ketimines and reductive amination of ketones,
giving fair to good yields and moderate enantioselectivity.
transfer H2 to a polar double bond (transfer hydrogenation). In
the presence of an excess of alcohol (typically iPrOH) or other
reducing agent (e.g. formic acid), this path leads to the reduction
of substrate’s C=O or C=N bond,[3,4a,9b] whereas Oppenauer-type
alcohol oxidation can be achieved in the presence of excess
ketone (e.g., acetone).[3b,e,10]
Introduction
In
recent
years,
the
catalytic
applications
of
(cyclopentadienone)iron complexes[ 1 ] (1 in Scheme 1) have
been increasingly studied. This growing interest is due to several
attractive features which distinguish this class of complexes from
most other Fe-based homogeneous catalysts:[ 2 ] i) they are
relatively easy to prepare and do not contain air-sensitive
phosphine ligands; ii) they are stable to air, moisture and column
chromatography; iii) they can be activated in situ by either de-
coordination of a CO ligand[3,4,5,6,7,8a-e,g] (Activation mode I in
Scheme 1)
or
conversion into the corresponding
(hydroxycyclopentadienyl)iron complexes 2 (Activation mode II
in Scheme 1).[8f,9]
Although
it
has
been
recently
reported
that
(cyclopentadienone)iron complexes can also promote C-N and
C-O bond-forming reactions,[7] most catalytic applications rely on
their ability to reversibly transfer H2 to polar double bonds,
following different pathways (Scheme 1). According to Path I,
the activated catalysts act-1 can dehydrogenate alcohols and
form the (hydroxycyclopentadienyl)iron complexes 2, which then
Scheme 1. Catalytic use of complexes 1 in reactions involving hydride transfer.
Moreover, redox-neutral reactions are also possible (Scheme 1,
path in green), in which an alcohol substrate – in the presence of
an amine – is oxidized and converted into an imine/iminium ion
that is then reduced without net hydrogen consumption
(‘hydrogen borrowing’ alcohol amination).[5,6,9a,c] Alternatively,
according to Path II (Scheme 1) complex act-1 can directly split
molecular hydrogen and form catalyst 2, which then reduces the
[a]
Dr. M. Cettolin, X. Bai, Dennis Lübken, M. Gatti, Dr. L. Pignataro,
Prof. Dr. C. Gennari
Università degli Studi di Milano, Dipartimento di Chimica
Via C. Golgi, 19 - 20133, Milan (Italy)
E-mail: cesare.gennari@unimi.it
substrate (hydrogenation[4b-e,8,9d-g]). In both Path
I and II,
hydrogen transfer occurs through a pericyclic transition state
involving both the iron atom and the ‘non-innocent’ ligand
swinging between the cyclopentadienone (act-1) and the
hydroxycyclopentadienyl form (2).[9h,i,11]
luca.pignataro@unimi.it
http://sites.unimi.it/gennarigroup/
Dr. S. Vailati Facchini, Prof. Dr. U. Piarulli
Università degli Studi dell’Insubria, Dipartimento di Scienza e Alta
Tecnologia,
[b]
Via Valleggio, 11 - 22100 Como (Italy)
E-mail: umberto.piarulli@uninsubria.it
https://www.uninsubria.it/hpp/umberto.piarulli
Among the redox transformations promoted by complexes act-1
and 2, C=N reduction[ 12 ] is one of the most important and
probably the one with the largest potential for improvement.
Renaud and co-workers pioneered the reductive amination of
carbonyl compounds promoted by in situ activated
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201801348
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(cyclopentadienone)iron complexes under hydrogenation
conditions.[8c,d,g] However, this methodology suffers from several
limitations such as sub-optimal yields, high catalyst loading and
relatively narrow substrate scope, covering mostly aldehydes
and only a few ketones.
reductive amination of aldehydes and ketones was also
developed.[4a]
The present paper accounts for our efforts to further implement
the potential of (cyclopentadienone)iron complexes in C=N
reduction using pre-catalyst 1b, the chiral complex 1c[4d,e] and its
modified analog 1d (Figure 1 C).
Results and Discussion
First, pre-catalyst 1b was tested in the presence of reducing
agents different from iPrOH. The screening was carried out
using the N-arylimine S1, which Beller[9g] and Zhao[9b] reported
as poorly reactive in catalytic hydrogenation (CH) and in CTH
promoted by catalyst 2a in the absence of co-catalysts.
Table 1. Reduction of (E)-N-(4-methoxyphenyl)-1-phenylethan-1-imine S1
promoted by pre-catalyst 1b.[a]
Cat. loading
[mol%]
Conv.
[%][b]
#
Hydrogen donor
Solvent
1
2
3
4
5
6
iPrOH
5:2 FA/TEA[c]
5
5
iPrOH
-
72
38
[d]
H2
5
Toluene
CH3OH
Toluene
CH3OH
22
[d]
H2
5
60
[d]
H2
10
10
98
Figure 1. A: Scope limitations of the classical ‘Knölker complexes’ (1a and 2a)
in C=N reduction. B: Studies on pre-catalyst 1b described previously.[4a] C:
Studies on C=N reduction, including the use of chiral complexes 1c-d,
reported in this work. CTH = catalytic transfer hydrogenation; CH = catalytic
hydrogenation; ATH = asymmetric transfer hydrogenation; AH = asymmetric
hydrogenation.
[d]
H2
>99
[a] Reaction conditions: T = 70 °C, 18 h. C0,sub. = 0.4 M; [b] Determined by 1H
NMR of the crude reaction mixture; [c] FA
trimethylamine; [d] PH2 = 20 bar.
= formic acid; TEA =
As shown in Table 1, imine S1 was subjected to different
reduction conditions in the presence of in situ activated complex
act-1b. Catalyst activation, which was found critical in order to
obtain reproducible results, was performed by adding
Me3NO[8d,10] to a rather concentrated solution of 1b (Cprecat. ≥ 0.1
M) and then stirring for 20 min at r.t. before adding the substrate.
Replacing iPrOH, used in our previously reported CTH
methodology,[4a] with the FA/TEA azeotropic mixture (FA =
formic acid; TEA = triethylamine) led to a drop of conversion,
possibly because of rapid degradation of the active catalyst
occurring in the acidic reaction environment (Table 1, entry 2 vs.
1). Also switching from CTH (with iPrOH) to CH conditions led to
lower conversions (Table 1, entries 3-4 vs. 1), which could be
improved only by increasing the catalyst loading to 10 mol%
(entries 5-6). These results led us to opt for CTH with iPrOH as
the optimal reduction method for expanding the application
scope of pre-catalyst 1b.
In general, the act-1- or 2-promoted reduction of ketimines
(either generated in situ from ketones, or pre-isolated) proved a
challenging task, which was achieved by Zhao (in transfer
hydrogenation)[9b] and Beller (in highly efficient and
enantioselective hydrogenation)[9d-g] employing, respectively, a
Lewis acid and a chiral Brønsted acid co-catalyst. Besides
intrinsically poor atom economy (two catalysts for a single
transformation), the latter approach has the limitation of
employing mostly the isolated complexes 2, which are sensitive
to air and light. Last but not least, no chiral type-1 or type-2
complex has been yet developed to achieve the enantioselective
hydrogenation of ketimines in the absence of chiral co-catalysts.
In a recent communication,[4a] we reported our efforts to develop
more efficient C=N bond reduction protocols building on the
(cyclopentadienone)iron complex 1b (Figure 1 B), previously
synthesized in our labs[4b] and found to be a remarkably more
active reduction pre-catalyst than the classical ‘Knölker
complexes’ 1a and 2a. Unlike the latter (Figure 1 A),[9g] catalyst
1b is able, upon activation with Me3NO, to promote the catalytic
transfer hydrogenation (CTH) of acetophenone-derived
ketimines (Figure 1 B) and other ketimines/aldimines in good
yields using relatively low loading (0.5-2 mol%). Exploiting the
high activity of pre-catalyst 1b, a CTH-based protocol for the
We thus tested pre-catalyst 1b with a number of aldimine
substrates under the previously established optimal conditions[4a]
(iPrOH, 100 °C, C0,sub. = 0.25 M, 1 mol% catalyst loading),
obtaining the results shown in Table 2. All reactions were carried
out on 0.5 mmol scale, and the yield of isolated product was
calculated in each case. All the N-p-methoxyphenyl (PMP)
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Table 2. Extension of scope evaluation in imine CTH promoted by pre-catalyst
aldimines (Table 2, entries 1, 3-5) were reduced in nearly
quantitative yield with the exception of the 4-nitroaniline-derived
imine S3 (entry 2). Remarkably, imine reduction occurred
chemoselectively and the reducible groups of substrates S3 and
S4 (-NO2 and -CN, respectively) remained unaffected under the
experimental conditions. Notably, also the heterocyclic
substrates S5 and S6 (Table 2, entries 4-5) reacted smoothly,
despite the presence of a heteroatom which could potentially
poison the Fe center. We next varied the imine N-substituent, to
ascertain its effect on reactivity: as expected, the N-phenyl-
protected substrates S7 and S8 reacted in high yields (Table 2,
entries 6-7). The N-benzylimines S9, S10 and S11 showed
lower reactivity compared to their N-aryl counterparts S5 and S6
(Table 2, entries 8-10 vs. 4-5).[13] Substrate S12, possessing the
easily removable benzhydryl protecting group at nitrogen, gave
similar yield to the N-benzyl substituted analog S9 (Table 2,
entry 11 vs. 8). Three ketimine substrates were also tested
(Table 2, entries 12-14), as a complement to the screening
previously reported by our group.[4a] In these reactions, 2 mol%
catalyst loading was used due to the lower reactivity of ketimines
compared to aldimines. The acetophenone-derived substrate
1b.[a]
Yield
[%][b]
Yield
[%][b]
#
1
Substrate
#
8
Substrate
99
46
99
66
36[c]
66
2
3
9
10
4
5
99
99
11
12
67
68[d]
S13, bearing
a bromine substituent that allows further
99[d]
99[d]
functionalization by cross-coupling chemistry, was converted in
good yield and without trace of de-bromination byproduct (Table
2, entry 12). Ketimines S14 and S15, deriving from aliphatic
ketones, were also included in the screening and underwent
CTH in quantitative yield (Table 2, entries 13-14), thus
demonstrating that the application scope of 1b is not restricted
to aryl ketones.
6
7
99
99
13
14
[a] Reaction conditions: substrate/1b/Me3NO = 100:1:2, C0,sub.= 0.25 M (0.5
mmol), T = 100 °C, 18 h, solvent: iPrOH. PMP = p-methoxyphenyl; [b] Isolated
yields; [c] NMR yield; [d] Substrate/1b/Me3NO = 100:2:4.
To get additional information on the catalytic properties of
complex 1b in C=N reduction, we set to study the kinetics of
ketimine S1 CTH (see Scheme Table 1) promoted by this pre-
catalyst.
Figure 2. Kinetics of the CTH of S1 promoted by complex 1b:
solvent: iPrOH; C0,S1 = 0.25 M (0.5 mmol); T = 100 °C; Ccat. = 12.5 mM.
•
Conversion to of P1 (GC);
•
Percent of unreacted S1. Conditions: S1/1b/Me3NO =100:5:10;
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The reaction was run in iPrOH at 100 °C in the presence of 5
mol% 1b and 10 mol% Me3NO, and conversion was determined
by GC analysis of samples taken at regular intervals (every 15
min in the first 3 h and later every 30 min). As can be seen in
Figure 2, the reaction showed pseudo-first order dependence on
substrate concentration, S1 having a half-life of 98.9 min under
the experimental conditions, corresponding to an average TOF
of 6.07 h-1 at 50% conversion. A comparison with the classical
Knölker complex 1a is not possible, since very low conversions
(2%) were obtained with this complex in the same reaction.[4a]
Following the successful use of 1b-promoted CTH in the
reductive amination of aldehydes and ketones,[4a] in this work we
devoted additional efforts to study the scope of this attractive
methodology. As already reported, effective and reproducible
imine formation was found crucial for success of reductive
amination, the best conditions[4a] being exemplified in Scheme 2.
substrates were screened in combination with p-anisidine and
phenethylamine, giving the results shown in Table 3. Both an
aromatic and a heteroaromatic substrate (Table 3, entries 1 and
3, respectively) were converted into the corresponding N-PMP
amines in excellent yields, whereas the sterically hindered
salicylaldehyde formed product P18 in only 44% yield (entry 2).
Isobutyraldehyde showed poor reactivity (Table 3, entry 4),
whereas the in situ formed N-alkyl imines proved reactive and
formed the corresponding products P20 and P21 in fair to good
yield (entries 5-6).
Next, the more challenging ketone reductive amination was
performed by screening a series of ketones in the presence of
p-anisidine. In these experiments, N,N-diisopropylethylamine
(DIPEA - 15 mol%) was added to the mixture before the
activated catalyst, in order to quench the catalytic amount (10
mol%) of trifluoroacetic acid (TFA) previously added to
accelerate imine formation, which would otherwise degrade the
catalyst act-1b.[4a] Delightfully, both aromatic (Table 4, entries 1,
3 and 5) and aliphatic ketones (entries 2, 4) were converted into
the corresponding N-PMP-amines in moderate to good yields
(ranging from 31% to 68%), including the challenging cyclic
substrates (entries 2 and 5).
Table 4. CTH-based reductive amination of ketones promoted by pre-catalyst
1b.[a,b]
Scheme 2. Examples of optimized conditions[4a] for the in situ formation of
aldimines (A) and ketimines (B). TFA = trifluoroacetic acid.
Table 3. CTH-based reductive amination of aldehydes promoted by pre-
catalyst 1b.[a,b]
Yield
[%][c]
Yield
[%][c]
#
1
Product
#
4
Product
31
52
51
Yield
[%][c]
Yield
[%][c]
#
1
Product
#
4
Product
2
3
41
68
5
99
17[d]
2
3
44
5
6
38
[a] Reaction conditions: ketone/amine/1b/Me3NO
=
100:150:5:5. Imine
formation: toluene, 100 °C, 3 Å MS (400 mg), TFA (10 mol%), 2 h. Catalyst
activation: iPrOH, Me3NO, r.t., 20 min. CTH: 3:1 iPrOH / toluene, C0,sub. in CTH
= 0.25 M (0.5 mmol), DIPEA (15 mol%), 100 °C, 18 h; [b] Toluene and DIPEA
were freshly distilled over sodium/benzophenone and CaH2, respectively; [c]
Isolated yields.
98
67
[a] Reaction conditions: aldehyde/amine/1b/Me3NO
=
100:150:5:5. Imine
formation: toluene, 100 °C, 3 Å MS (400 mg), 1 h. Catalyst activation: iPrOH,
Me3NO, r.t., 20 min. CTH: 3:1 iPrOH/toluene, C0,sub. in CTH = 0.25 M (0.5
mmol), 100 °C, 18 h; [b] The aldehydes used were distilled over PPh3 prior to
use; [c] Isolated yields; [d] Yield determined by 1H NMR.
In 2015, our research group reported a new class of BINOL-
derived chiral (cyclopentadienone)iron complexes, and their use
in the asymmetric hydrogenation (AH) of ketones.[4d,e] These
pre-catalysts proved slightly less active than the ‘Knölker
We thus screened a number of new aldehyde (Table 3) and
ketone substrates (Table 4) following the optimized reductive
amination protocol:[4a] pre-catalyst 1b was activated with Me3NO
in iPrOH, and then added to the imine generated in situ in
toluene, so that reduction was carried out in a 3:1 iPrOH/toluene
mixture. Compared to the CTH of isolated imines, the catalyst
loading was slightly increased (to 5 mol%) due to the more
challenging nature of reductive amination. The aldehyde
complex’ 1a (Figure
1
A) and showed
a
moderate
enantioselectivity (up to 77% ee with the best complex 1c,
shown in Figure 1 C).[1a] Building on the experience gained in the
transfer hydrogenation of imines with complex 1b, we decided to
test our chiral complexes also in the asymmetric transfer
hydrogenation (ATH) of ketimines. Although – as mentioned
above – most (cyclopentadienone)iron complexes are not
sufficiently active to promote the reduction of ketimines,[9f] Zhao
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and co-workers recently reported that the latter substrates can
be activated in the presence of a Lewis acid co-catalyst.[9b]
However, a preliminary test of pre-catalyst 1c in the presence of
Me3NO and Fe(acac)3 in the CTH of ketimine S1 gave no
conversion (Table 5, entry 1).
In the attempt to increase the reactivity of the cyclopentadienone
iron complex, pre-catalyst 1d was prepared by dissociation of
one CO ligand by Me3NO and replacement with benzonitrile
(Scheme 3). In this case the activated form act-1d can be
obtained by thermal dissociation of the labile nitrile ligand.[14]
Table 6. Ketimine ATH promoted by pre-catalyst 1d.[a]
#
1
Substrate
Conv. [%][b]
44
ee [%]
33, R[c]
2
3
38
0
24, R[d]
-
[a] Reaction conditions: imine/1d/Fe(acac)3 = 100:5:20; solvent: iPrOH, C0,sub.
= 0.5 M (1 mmol), T = 110 °C, 48 h; [b] Determined by 1H NMR; [c] Determined
by chiral HPLC. Absolute configuration assigned by comparing the order of
elution with literature data (see the Supporting Information); [d] Determined by
chiral HPLC. Absolute configuration assigned by comparison of the optical
rotation sign (see the Supporting Information).
Scheme 3. Synthesis of the nitrile-substituted chiral complex 1d.
We tested the catalytic activity of complex 1d in the CTH of N-(4-
methoxyphenyl)-1-phenylethan-1-imine S1 in the presence of
several Lewis acids (see Supporting Information and Table 5).
Table 7. Ketimine AH promoted by pre-catalyst 1d.[a]
Table 5. Optimization of the imine S1 ATH promoted by chiral pre-catalysts
1c-d.[a]
#
1
Substrate
Conv. [%][b]
81
ee [%]
33, R[c]
Amount of Lewis acid
#
1
2
3
4
5
6
Pre-cat.
1c[c]
1d
Lewis acid
Fe(acac)3
-
Conv. [%][b]
[mol%]
40
0
2
3
99
74
7, R[c]
-
0
31, (+)[e]
1d
Fe(acac)3
Fe(acac)3
Fe(acac)3
AgF
10
20
40
40
12
44
36
25
1d
[a] Reaction conditions: imine/1d/Fe(acac)3 = 100:5:20; H2 (50 bar); solvent:
MeOH, C0,sub. = 0.5 M (0.5 mmol), T = 85 °C, 18 h; [b] Determined by 1H NMR;
[c] See footnotes [c] and [d] of Table 6; [e] Determined by chiral HPLC: no
correlation between sign of optical rotation and absolute configuration has
been established so far.
1d
1d
[a] Reaction conditions: S1/Pre-cat. = 100:5, solvent: iPrOH, T = 110 °C, 48 h,
C0,S1 = 0.5 M (1 mmol); [b] Determined by 1H NMR; [c] Complex 1c pre-
activated in the presence of 10 mol% Me3NO for 20 min at r.t..
Finally, we tried to establish an enantioselective reductive
amination protocol based on complex 1d. As this pre-catalyst
showed higher activity in CH than in CTH (see Table 7 vs. Table
6), we decided to use hydrogenation for the reduction step. Thus,
after imine formation (run in MeOH at reflux for 1 h), pre-catalyst
1d (5 mol% loading) was added and then the mixture was
reacted overnight at 85 °C under 50 bar of H2. As shown in
Table 8, the reductive amination of acetophenone and 4-
chloroacetophenone proceeded, respectively, in good and fair
yield and with a level of enantioselectivity quite modest but
slightly higher than the one observed for isolated ketimines S1
and S26 (see Table 6 and 7).
As expected, no conversion was obtained without Lewis acid
(Table 5, entry 2). On the contrary, appreciable conversions
were achieved in the presence of Fe(acac)3 (Table 5, entries 3-
5) and AgF (entry 6), 20 mol% of the former giving the best
result (entry 4). Under the optimized conditions, three ketimines
were screened, giving the results shown in Table 6: substrates
S1 and S22 were reduced with moderate conversion and poor
enantioselectivity (entries 1 and 2), whereas imine S26 did not
react at all (entry 3). The 1d/Fe(acac)3 catalytic system was also
tested under hydrogenation conditions, in order to possibly
achieve better conversion than in the ATH protocol. As shown in
Table 7, good conversions were indeed obtained for all the three
substrates, but unfortunately the level of enantioselectivity
remained similar to the one observed in ATH.
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Table 8. CH-based reductive amination of ketones promoted by pre-catalyst
1d.[a]
solution. Flash Column Chromatography was performed using silica gel
(60 Å, particle size 40-64 μm) as stationary phase, following the
procedure by Still and co-workers.[15] 1H NMR spectra were recorded on
a spectrometer operating at 400.13 MHz. Proton chemical shifts are
reported in ppm (δ) with the solvent reference relative to
tetramethylsilane (TMS) employed as the internal standard (CDCl3, δ =
7.26 ppm; CD2Cl2 δ = 5.32 ppm; acetone-d6, δ = 2.05 ppm; toluene-d8, δ
= 2.08 ppm; CD3OD, δ = 3.31 ppm). The following abbreviations are used
to describe spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad signal, dd = doublet-doublet, ddd = doublet-
doublet-doublet, td = triplet-doublet. 13C NMR spectra were recorded
either on a 400 MHz spectrometer operating at 100 MHz or on a 600
MHz spectrometer operating at 150 MHz, with complete proton
decoupling. Carbon chemical shifts are reported in ppm (δ) relative to
TMS with the respective solvent resonance as the internal standard
(CDCl3 δ = 77.16 ppm; CD2Cl2 δ = 54.00 ppm; acetone-d6 δ = 29.84 ppm,
206.26 ppm; CD3OD, δ = 49.00 ppm). The coupling constant values are
given in Hz. Infrared spectra were recorded on a standard FT/IR
spectrometer. High resolution mass spectra (HRMS) were performed on
#
1
Product
Yield [%][b]
68
ee [%][c]
42
2
33
47
[a] Reaction conditions: ketone/amine/1d = 100:120:5. Imine formation: MeOH,
reflux, 1 h. CH: MeOH, C0,sub. in CTH = 0.5 M (0.2 mmol), 85 °C, 18 h; [b]
Isolated yields; [c] Determined by chiral HPLC on the amine derivatives (Boc
for P27 and Bz for P28).
a
Fourier Transform Ion Cyclotron Resonance (FT-ICR) Mass
Spectrometer APEX II & Xmass software (Bruker Daltonics) – 4.7 T
Magnet (Magnex) equipped with ESI source, available at the UNITECH-
COSPECT laboratories, at Università degli Studi di Milano.
Conclusions
The work described in this paper complements the results
a
previous communication,[4a] expanding the
Materials: commercially available reagents were used as received.
Ketones and aldehydes used in the substrate screening were purchased
from commercial suppliers (TCI Chemicals, ACROS, Sigma Aldrich) and
distilled over PPh3 before use. The other commercially available reagents
were used as received. 3 Å MS were dried under high vacuum at 200 °C
and then stored in an oven at 110 °C.
described in
application scope of (cyclopentadienone)iron complexes in C=N
reduction. Owing to the high catalytic activity of our recently
reported pre-catalyst 1b (Figure 1 B),[4a,b] it has been possible to
carry out C=N reductions which are usually very sluggish or
even impossible using the classical ‘Knölker complexes’ 1a and
2a (Figure 1 A): the application scope of pre-catalyst 1b has
been expanded to reducing agents different from iPrOH and to
the CTH of numerous additional aldimines and ketimines, both
pre-isolated and generated in situ according to a reductive
amination protocol. Additionally, the kinetics of CTH promoted
by pre-catalyst 1b have been assessed, showing a pseudo-first
order profile.
To further demonstrate the potential of (cyclopentadienone)iron
complexes in C=N reduction, we have tested chiral pre-catalyst
1c[4d,e] and its analog 1d (Figure 1 B) in the ATH and AH of
ketimines and in the reductive amination of ketones. Although
rather low ee values were obtained, the one described here is
the first example of imine enantioselective reduction promoted
by a chiral (cyclopentadienone)iron complex, and provides the
basis for the future development of more efficient catalysts.
General Procedure for the CTH of pre-formed imines
Pre-catalyst 1b (3.8 mg, 0.010 mmol, 0.02 equiv.) and Me3NO (1.6 mg,
0.020 mmol, 0.04 equiv.) were dissolved in dry iPrOH (0.1 mL) and the
resulting solution, which gradually turned from yellow to dark red, was
stirred for 20 minutes at r.t.. The imine substrate (0.5 mmol, 1 equiv.) was
added, followed by dry iPrOH (1.9 mL). The reaction vessel was sealed
and stirred in a pre-heated oil bath at 100 °C for 18 h. After cooling down,
the mixture was filtered through a celite pad (rinsing with AcOEt), the
volatiles were removed and the product was purified by flash column
chromatography (hexane/AcOEt mixtures with 0.5-1% Et3N).
General Procedure for the reductive amination of aldehydes
3 Å MS (400 mg), aldehyde (0.5 mmol, 1 equiv.) and amine (0.75 mmol,
1.5 equiv.) were dissolved in dry toluene (0.5 mL) and the mixture was
stirred for 1 h at 100 °C. Meanwhile, in another vessel, pre-catalyst 1 (9.6
mg, 0.025 mmol, 0.05 equiv.) and Me3NO (1.9 mg, 0.025 mmol, 0.05
equiv.) were dissolved in dry iPrOH (0.25 mL) and stirred for 20 min at r.t..
The activated catalyst solution was dispensed into the vessel containing
the imine, followed by dry iPrOH (1.25 mL). The reaction vessel was
sealed and stirred in a pre-heated oil bath at 100 °C for 18 h. After
cooling down, the mixture was filtered through a celite pad (rinsing with
AcOEt), the volatiles were removed and the crude was purified by flash
column chromatography (hexane/AcOEt mixtures with 0.5-1% Et3N).
Experimental Section
All reactions were carried out in flame-dried glassware with magnetic
stirring under inert atmosphere (nitrogen or argon), unless otherwise
stated. Solvents for reactions were distilled over the following drying
agents and transferred under nitrogen: CH2Cl2 (CaH2), MeOH (CaH2),
toluene (Na/benzophenone). Dry 2-propanol (over molecular sieves in
bottles with crown cap) was purchased from Sigma Aldrich and stored
under nitrogen. The reactions were monitored by analytical thin-layer
chromatography (TLC) using silica gel 60 F254 pre-coated glass plates
(0.25 mm thickness). Visualization was accomplished by irradiation with
a UV lamp and/or staining with a potassium permanganate alkaline
General Procedure for the reductive amination of ketones
3 Å MS (400 mg), ketone (0.5 mmol, 1 equiv.), amine (0.75 mmol, 1.5
equiv.) and TFA (4 μL, 0.05 mmol, 0.1 equiv., dispensed as a stock
solution in toluene) were dissolved in dry toluene (final total volume: 0.5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801348
European Journal of Organic Chemistry
FULL PAPER
mL) and stirred for 2 h at 100 °C. Meanwhile, in another vessel, pre-
catalyst 1 (9.6 mg, 0.025 mmol, 0.05 equiv.) and Me3NO (1.9 mg, 0.025
mmol, 0.05 equiv.) were dissolved in dry iPrOH (0.25 mL) and stirred for
20 min at r.t.. Freshly distilled DIPEA (13 μL, 0.075 mmol, 0.15 equiv.)
and then the activated catalyst solution were dispensed into the vessel
containing the imine, followed by dry iPrOH (1.25 mL). The reaction
vessel was sealed and stirred at 100 °C for 18 h. After cooling down, the
mixture was filtered through a celite pad (rinsing with AcOEt), the
volatiles were removed and the crude was purified by flash column
chromatography (hexane/AcOEt mixtures with 0.5-1% Et3N).
DCM (0.5 mL) and hydrochloric acid (1 M, 0.5 mL) was added. The two-
phase mixture was stirred for 3 h. at r.t. before basifying with 1
M
aqueous NaOH. The aqueous layer was extracted with AcOEt (3 × 5 mL)
and the combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. Flash chromatography
(hexane/AcOEt mixtures with 0.5-1% Et3N) afforded the amine product.
Ninhydrin staining allowed to visualize the product amine (pale red spot)
and p-anisidine (dark red spot).
General Procedure for the enantioselective reductive amination of
ketones using complex 1d
Synthesis of complex 1d
A 10 mL flame-dried autoclave vial containing a stirring bar was charged
with ketone (0.2 mmol, 1.0 equiv., 0.5 M), phenethylamine (29 mg, 0.24
mmol, 1.2 equiv.) and dry MeOH (0.27 mL) under argon. The reaction
mixture was heated to reflux in the sealed autoclave vial for 1 h. A
solution of complex 1d (7.9 mg, 0.01 mmol, 0.05 equiv.) in dry methanol
(0.13 mL) was then added to the autoclave vial. The autoclave was
pressurized to the final pressure of hydrogen (50 bar) and stirred at 85 °C
for 18 h. After cooling down to r.t. and careful venting of remaining
hydrogen, the reaction mixture was filtered over deactivated neutral
alumina (3% of H2O) rinsing with AcOEt. After removing the solvent
under reduced pressure, the product was purified by flash column
chromatography (hexane/AcOEt mixtures with 0.5-1% Et3N).
To a stirred solution of 1c (100 mg, 0.19 mmol, 1.0 equiv.) in dry acetone
(11.5 mL) under argon atmosphere, trimethylamine N-oxide (16 mg, 0.21
mmol, 1.2 equiv.) and benzonitrile (38 μL, 0.37 mmol, 2.0 equiv.) were
added. The reaction was refluxed for 20 hours in a sealed tube. After
cooling down the reaction to r.t., the solvent was removed under reduced
pressure. Flash chromatography (1:1 hexane/DCM, then 8:2
hexane/AcOEt) afforded the product 1d as a yellow solid. Yield: 77 mg
(58%); m.p. = 184-186 °C; [α]D20 = -13.4 (c = 0.13 in DCM); 1H NMR (400
MHz, 9:1 CDCl3 / CD3OD): δ 7.75 (t, J = 8.6 Hz, 2H), 7.66 (d, J = 5.8 Hz,
2H), 7.54 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.32 (dd, J = 12, 7.4
Hz, 2H), 7.25 (s, 1H), 7.20 (s, 1H), 7.00 (dd, J = 14.7, 7.3 Hz, 2H), 6.82
(dd, J = 7.6, 6.4 Hz, 2H), 4.25 (d, J = 15.3 Hz, 1H), 3.99 (s, 3H), 3.90 (s,
3H), 3.31 (s, 2H), 2.84 (dd, J = 31.3, 15.2 Hz, 2H), 0.31 (s, 9H), 0.22 (s,
9H); 13C NMR (150 MHz, 9:1 CDCl3 / CD3OD): δ 212.58, 211.82, 178.84,
168.27, 156.30, 155.15, 154.92, 138.15, 137.75, 136.85, 133.80, 133.60,
133.47, 133.27, 132.61, 129.13, 128.24, 127.95, 127.30, 127.15, 126.76,
126.62, 126.17, 126.04, 123.87, 123.61, 111.94, 105.76, 105.32, 105.08,
73.09, 55.25, 55.10, 54.53, 29.82, 25.80, 0.38; FT-IR: ν = 2954.1, 2922.6,
2898.5, 2851.2, 2299.7, 2058.6, 2003.7, 1947.8, 1677.8, 1618.0, 1593.9,
1446.4, 1422.2, 1407.8, 1328.7, 1238.1, 1195.7, 1109.8, 1018.2, 852.4,
841.8, 745.4, 617.1 cm-1; HRMS (ESI+): m/z 778.21433 [M + H]+ (calcd.
for C44H43FeNO5Si2: 778.21074).
Acknowledgements
X. Bai thanks the China Scholarship Council for a PhD
fellowship (CSC No. 201608410107). D. Lübken thanks the
Erasmus+ Programme for a fellowship. L. Pignataro thanks the
Dipartimento di Chimica, Università degli Studi di Milano, for
financial support (Piano di Sostegno alla Ricerca 2015–2017).
Keywords: transfer hydrogenation • iron • amination • imines •
asymmetric catalysis
General Procedure for the ATH of ketimines using complexes 1d
A flame dried Schlenk tube containing a stirring bar was charged with
imine (0.5 mmol, 1.0 equiv.), Fe(acac)3 (20 mol%), pre-catalyst 1d (5
mol%) and dry iPrOH (1 mL) under argon atmosphere. The reaction
mixture was stirred at 110 °C (preheated oil bath) for 48 h. The reaction
mixture was cooled down to r.t. and then filtered over deactivated neutral
alumina (3% of H2O) and rinsed with AcOEt. After removing the solvent
under reduced pressure, the crude was dissolved in DCM (0.5 mL) and 1
M hydrochloric acid (0.5 mL) was added. The two-phase mixture was
stirred for 3 h at r.t. before basifying with 1 M aqueous NaOH. The
aqueous layer was extracted with AcOEt (3 × 5 mL) and the combined
organic layers dried over Na2SO4 and concentrated under reduced
pressure. Flash chromatography (hexane/AcOEt mixtures with 0.5-1%
Et3N) afforded the product amine. Ninhydrin staining visualizes the
product amine (pale red spot) and p-anisidine (dark red spot).
[1] For reviews on catalytic applications of (cyclopentadienone)iron
complexes, see: a) U. Piarulli, S. Vailati Facchini, L. Pignataro, Chimia
2017, 71, 580-585; b) A. Quintard, J. Rodriguez, Angew. Chem. Int. Ed.
2014, 53, 4044-4055; Angew. Chem. 2014, 126, 4124-4136.
[2] For general reviews on homogeneous iron catalysis, see: a) I. Bauer, H.-J.
Knölker, Chem. Rev. 2015, 115, 3170-3387; b) K. Gopalaiah, Chem. Rev.
2013, 113, 3248-3296; c) M. Darwish, M. Wills, Catal. Sci. Technol. 2012,
2, 243-255; d) W. M. Czaplik, M. Mayer, J. Cvengroš, A. Jacobi von
Wangelin, ChemSusChem 2009, 2, 396-417; e) S. Enthaler, K. Junge, M.
Beller, Angew. Chem. Int. Ed. 2008, 47, 3317-3321; Angew. Chem. 2008,
120, 3363-3367; f) C. Bolm, J. Legros, J. Le Paih, L. Zani, Chem. Rev.
2004, 104, 6217-6254.
[3] a) A. Del Grosso, A. E. Chamberlain, G. J. Clarkson, M. Wills, Dalton
Trans. 2018, 47, 1451-1470; b) T. W. Funk, A. R. Mahoney, R. A.
Sponenburg, K. P. Zimmerman, D. K. Kim, E. E. Harrison,
Organometallics 2018, 37, 1133-1140; c) R. Hodgkinson, A. Del Grosso,
G. Clarkson, M. Wills, Dalton Trans. 2016, 45, 3992-4005; d) J. P.
Hopewell, J. E. D. Martins, T. C. Johnson, J. Godfrey, M. Wills, Org.
Biomol. Chem. 2012, 10, 134-145; e) T. N. Plank, J. L. Drake, D. K. Kim,
T. W. Funk, Adv. Synth. Catal. 2012, 354, 597-601; f) T. C. Johnson, G. J.
Clarkson, M. Wills, Organometallics 2011, 30, 1859-1868.
General Procedure for the AH of ketimines using complex 1d
A 10 mL flame-dried autoclave vial containing a stirring bar was charged
with imine (0.5 mmol, 1.0 equiv.), Fe(acac)3 (20 mol%), pre-catalyst 1d (5
mol%) and dry methanol (1 mL) under argon atmosphere. The autoclave
was pressurized to 50 bars of hydrogen and stirred at 85 °C for 18 h. The
reaction mixture was cooled down to r.t. and then filtered over
deactivated neutral alumina (3% of H2O) and rinsed with AcOEt. After
removing the solvent under reduced pressure, the crude was dissolved in
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801348
European Journal of Organic Chemistry
FULL PAPER
[4] a) S. Vailati Facchini, M. Cettolin, X. Bai, G. Casamassima, L. Pignataro,
C. Gennari, U. Piarulli, Adv. Synth. Catal. 2018, 360, 1054-1059; b) S.
Vailati Facchini, J.-M. Neudörfl, L. Pignataro, M. Cettolin, C. Gennari, A.
Berkessel, U. Piarulli, ChemCatChem 2017, 9, 1461-1468; c) P.
Gajewski, A. Gonzalez-de-Castro, M. Renom-Carrasco, U. Piarulli, C.
Gennari, J. G. de Vries, L. Lefort, L. Pignataro, ChemCatChem 2016, 8,
3431-3435; d) P. Gajewski, M. Renom-Carrasco, S. Vailati Facchini, L.
Pignataro, L. Lefort, J. G. de Vries, R. Ferraccioli, U. Piarulli, C. Gennari,
Eur. J. Org. Chem. 2015, 5526-5536; e) P. Gajewski, M. Renom-
Carrasco, S. Vailati Facchini, L. Pignataro, L. Lefort, J. G. de Vries, R.
Ferraccioli, A. Forni, U. Piarulli, C. Gennari, Eur. J. Org. Chem. 2015,
1887-1893.
b) H.-J. Pan, T. W. Ng, Y. Zhao, Org. Biomol. Chem. 2016, 14, 5490-
5493; c) H.-J. Pan, T. W. Ng, Y. Zhao, Chem. Commun. 2015, 51, 11907-
11910; d) S. Zhou, S. Fleischer, H. Jiao, K. Junge, M. Beller, Adv. Synth.
Catal. 2014, 356, 3451-3455; e) S. Fleischer, S. Zhou, S. Werkmeister, K.
Junge, M. Beller, Chem. Eur. J. 2013, 19, 4997-5003; f) S. Fleischer, S.
Werkmeister, S. Zhou, K. Junge, M. Beller, Chem. Eur. J. 2012, 18, 9005-
9010; g) S. Zhou, S. Fleischer, K. Junge, M. Beller, Angew. Chem. Int.
Ed. 2011, 50, 5120-5124; Angew. Chem. 2011, 123, 5226-5230; h) M. G.
Coleman, A. N. Brown, B. A. Bolton, H. Guan, Adv. Synth. Catal. 2010,
352, 967-970; i) C. P. Casey, H. Guan, J. Am. Chem. Soc. 2009, 131,
2499-2507; l) C. P. Casey, H. Guan, J. Am. Chem. Soc. 2007, 129, 5816-
5817.
[5] For use of (cyclopentadienone)iron complexes in the ‘hydrogen
borrowing’ amination of alcohols, see: a) K. Polidano, B. D. W. Allen, J. M.
J. Williams, L. C. Morrill, ACS Catal. 2018, 8, 6440-6445; b) T. Yan, B. L.
Feringa, K. Barta, Sci. Adv. 2017, 3, eaao6494; c) M. Vayer, S. P.
Morcillo, J. Dupont, V. Gandon, C. Bour, Angew. Chem. Int. Ed. 2018, 57,
3228-3232; Angew. Chem. 2018, 130, 3282-3286; d) T. J. Brown, M.
Cumbes, L. J. Diorazio, G. J. Clarkson, M. Wills, J. Org. Chem. 2017, 82,
10489-10503; e) T. Yan, B. L. Feringa, K. Barta, ACS Catal. 2016, 6, 381-
388; f) A. Quintard, J. Rodriguez, ChemSusChem 2016, 9, 28-30; g) A. J.
Rawlings, L. J. Diorazio, M. Wills, Org. Lett. 2015, 17, 1086-1089; h) H.-J.
Pan, T. W. Ng, Y. Zhao, Chem. Commun. 2015, 51, 11907-11910; i) T.
Yan, B. L. Feringa, K. Barta, Nat. Commun. 2014, 5, 5602.
[10] S. A. Moyer, T. W. Funk, Tetrahedron Lett. 2010, 51, 5430-5433.
[11] a) H. Ge, X. Chen, X. Yang, Chem. Commun. 2016, 52, 12422-12425; b)
X. Lu, Y. Zhang, P. Yun, M. Zhang, T. Li, Org. Biomol. Chem. 2013, 11,
5264-5277; c) A. von der Höh, A. Berkessel, ChemCatChem 2011, 3,
861-867; d) H. Zhang, D. Chen, Y. Zhang, G. Zhang, J. Liu, Dalton Trans.
2010, 39, 1972-1978.
[12] For general reviews on C=N reductions, see: a) P.-G. Echeverria, T.
Ayad, P. Phansavath, V. Ratovelomanana-Vidal, Synthesis 2016, 48,
2523-2539; b) C. Claver, E. Fernández, in Modern Reduction Methods,
Wiley-VCH, 2008, pp. 235-269; c) M. Wills, in Modern Reduction Methods,
Wiley-VCH, 2008, pp. 271-296.
[13] For the N-PMP analog of imine S9, see Ref. [4a].
[6] For use of (cyclopentadienone)iron complexes in hydrogen auto-transfer
reactions different from alcohol amination, see: a) Ref. [5a]; b) S.
Elangovan, J.-B. Sortais, M. Beller, C. Darcel, Angew. Chem. Int. Ed.
2015, 54, 14483-14486; c) M. Roudier, T. Constantieux, A. Quintard, J.
Rodriguez, Org. Lett. 2014, 16, 2802-2805; d) A. Quintard, T.
Constantieux, J. Rodriguez, Angew. Chem. Int. Ed. 2013, 52, 12883-
12887; Angew. Chem. 2013, 125, 13121-13125.
[14] For previous examples of (cyclopentadienone)iron complexes bearing a
nitrile ligand, see Ref. [3d,8c].
[15] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923-2925.
[7] a) A. Guđmundsson, K. P. J. Gustafson, B. K. Mai, B. Yang, F. Himo, J.-
E. Bäckvall, ACS Catal. 2018, 8, 12-16; b) O. El-Sepelgy, A. Brzozowska,
J. Sklyaruk, Y. K. Jang, V. Zubar, M. Rueping, Org. Lett. 2018, 20, 696-
699; c) O. El-Sepelgy, A. Brzozowska, L. M. Azofra, Y. K. Jang, L.
Cavallo, M. Rueping, Angew. Chem. Int. Ed. 2017, 56, 14863-14867;
Angew. Chem. 2017, 129, 15059-15063.
[8] a) A. Lator, S. Gaillard, A. Poater, J.-L. Renaud, Chem. Eur. J. 2018, 24,
5770-5774; b) D. Brenna, S. Rossi, F. Cozzi, M. Benaglia, Org. Biomol.
Chem. 2017, 15, 5685-5688; c) T.-T. Thai, D. S. Mérel, A. Poater, S.
Gaillard, J.-L. Renaud, Chem. Eur. J. 2015, 21, 7066-7070; d) S. Moulin,
H. Dentel, A. Pagnoux-Ozherelyeva, S. Gaillard, A. Poater, L. Cavallo, J.-
F. Lohier, J.-L. Renaud, Chem. Eur. J. 2013, 19, 17881-17890; e) D. S.
Mérel, M. Elie, J.-F. Lohier, S. Gaillard, J.-L. Renaud, ChemCatChem
2013, 5, 2939-2945; f) S. Fleischer, S. Zhou, K. Junge, M. Beller, Angew.
Chem. Int. Ed. 2013, 52, 5120-5124; Angew. Chem. 2013, 125, 5224-
5228; g) A. Pagnoux-Ozherelyeva, N. Pannetier, M. D. Mbaye, S.
Gaillard, J.-L. Renaud, Angew. Chem. Int. Ed. 2012, 51, 4976-4980;
Angew. Chem. 2012, 124, 5060-5064; h) A. Tlili, J. Schranck, H.
Neumann, M. Beller, Chem. Eur. J. 2012, 18, 15935-15939; i) A.
Berkessel, S. Reichau, A. von der Höh, N. Leconte, J.-M. Neudörfl,
Organometallics 2011, 30, 3880-3887.
[9] For the use of isolated (hydroxycyclopentadienyl)iron complexes in
catalysis, see: a) O. El-Sepelgy, N. Alandini, M. Rueping, Angew. Chem.
Int. Ed. 2016, 55, 13602-13605; Angew. Chem. 2016, 128, 13800-13803;
This article is protected by copyright. All rights reserved.