Chiral Cyclopentadienone iron complexes for the catalytic asymmetric hydrogenation of ketones

Article abstract of DOI:10.1002/ejoc.201500146

Three chiral (cyclopentadienone)iron complexes derived from (R)-BINOL (CK1-3) were synthesized and their structures unambiguously confirmed by X-ray analysis (CK3). Under suitable conditions for the in situ conversion into the corresponding (hydroxycyclopentadienyl)iron hydrides (Me₃NO, H₂), the new chiral complexes were tested in the catalytic asymmetric hydrogenation of ketones, showing moderate to good enantioselectivity. In particular, the complex bearing methoxy substituents at the 3,3-positions of the binaphthyl moiety (CK2) proved remarkably more enantioselective than the unsubstituted one (CK1) and reached the highest level of enantioselectivity (up to 77% ee) ever obtained with chiral (cyclopentadienone)iron complexes. Reducto! Chiral (cyclopentadienone)iron complexes were synthesized and tested, after in situ activation, in the catalytic asymmetric hydrogenation of ketones leading to the highest enantiomeric excesses ever obtained with this type of catalysts.

Full text of DOI:10.1002/ejoc.201500146

Job/Unit: O50146
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Pages: 8
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500146
Chiral (Cyclopentadienone)iron Complexes for the Catalytic Asymmetric
Hydrogenation of Ketones
Piotr Gajewski,[a,b] Marc Renom-Carrasco,
[a,b]
Sofia Vailati Facchini, Luca Pignataro,*
[c]
[a]
[b]
[d]
[e]
[e]
Laurent Lefort, Johannes G. de Vries, Raffaella Ferraccioli, Alessandra Forni,
[
c]
[a]
Umberto Piarulli,* and Cesare Gennari*
Keywords: Asymmetric catalysis / Hydrogenation / Chiral auxiliaries / Iron / Homogeneous catalysis / Ketones / Reduction
Three chiral (cyclopentadienone)iron complexes derived
from (R)-BINOL (CK1–3) were synthesized and their struc-
tures unambiguously confirmed by X-ray analysis (CK3).
Under suitable conditions for the in situ conversion into the
moderate to good enantioselectivity. In particular, the com-
plex bearing methoxy substituents at the 3,3Ј-positions of the
binaphthyl moiety (CK2) proved remarkably more enantio-
selective than the unsubstituted one (CK1) and reached the
highest level of enantioselectivity (up to 77% ee) ever ob-
tained with chiral (cyclopentadienone)iron complexes.
corresponding
(hydroxycyclopentadienyl)iron
hydrides
(
Me NO, H ), the new chiral complexes were tested in the
3
2
catalytic asymmetric hydrogenation of ketones, showing
[
5b,6]
Introduction
ketoimines,
olefins.
while no examples were reported with
[
7]
Asymmetric hydrogenation (AH) is by far the indus-
trially most relevant enantioselective transformation, owing
to its operational simplicity and 100% atom economy. Dur-
ing its history of 40 years, thousands of homogeneous cata-
lysts have been developed, allowing the hydrogenation of
many substrates with high enantioselectivity.[ However,
most of the AH catalysts rely on very expensive and toxic
precious metals (e.g., Ru, Rh, Ir, Pd), which may prevent in
some cases their implementation on a large scale.[ For this
reason, developing new catalysts relying on cheap “base
metals” (e.g., Fe, Co, Ni, Cu) constitutes the next frontier
to unleash the full potential of AH. In particular, Fe
appears to be the most appealing base metal due to its
abundance (5% of Earth’s crust), low cost and scarce
In our quest for new chiral Fe catalysts for the AH of
ketones, our attention was captured by (cyclopenta-
dienone)- and (hydroxycyclopentadienyl)iron complexes,
whose catalytic properties are currently the object of grow-
[
8]
ing interest. Although (cyclopentadienone)iron complexes
1]
[
9]
are known since the 1950s, it was only in 1999 that
Knölker and co-workers were able to isolate and character-
ize the hydroxycyclopentadienyl-activated complex act-K1,
obtained from (cyclopentadienone)iron complex K1 by
2]
[
10]
Hieber base reaction [Figure 1 (a)].
The catalytic poten-
tial of complex act-K1 was discovered some years later by
[
11a]
Casey and co-workers,
who reported its ability to pro-
mote the hydrogenation of carbonyl compounds and pro-
[
11b]
posed a concerted outer-sphere mechanism.
One limita-
[
3]
toxicity. In spite of these attractive features, the applica-
tion of act-K1-type complexes is their sensitivity to air and
moisture. However, it has been recently shown that this
problem can be circumvented by generating complexes act-
[4]
tion of Fe in AH is still very limited: a few chiral catalysts
[
5]
have been developed for the hydrogenation of ketones and
K in situ from their precursors K (stable to air, moisture
[
a] Università degli Studi di Milano, Dipartimento di Chimica
NO,[ UV
12]
Via C. Golgi 19, 20133 Milan, Italy
and chromatography) in the presence of Me
3
E-mail: luca.pignataro@unimi.it
[5c]
[13]
light or K CO3
[Figure 1 (b)]. Therefore, unlike most
2
cesare.gennari@unimi.it
other Fe complexes used in homogeneous hydrogen-
http://www.chimica.unimi.it/ecm/home
[
5b,5e,5f,14]
[
b] DSM Innovative Synthesis BV,
ation,
cyclopentadienone complexes K are stable
P. O. Box 18, 6160 MD Geleen, The Netherlands
c] Università degli Studi dell’Insubria, Dipartimento di Scienza e
Alta Tecnologia,
pre-catalysts, which do not require an inert or dry atmo-
sphere (e.g., use of a glovebox) to be handled. This attract-
ive feature makes them suitable candidates for practical in-
dustrial use. Chiral (cyclopentadienone)iron complexes have
[
Via Valleggio 11, 22100 Como, Italy
E-mail: umberto.piarulli@uninsubria.it
[
d] Leibniz-Institut für Katalyse e.V.
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
e] CNR, Istituto di Scienze e Tecnologie Molecolari (ISTM)
Via C. Golgi 19, 20133 Milan, Italy
been obtained either by replacing one of the CO ligands of
[
[5c]
a K complex with a chiral phosphoramidite,
or by
inserting a stereocenter on the ring fused to the cyclo-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500146.
[
12d]
pentadienone.
However, despite their theoretical inter-
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L. Pignataro, U. Piarulli, C. Gennari et al.
SHORT COMMUNICATION
Figure 1. Knölker’s synthesis of CpFe-activated complex act-K1 (a) and reported methods for in situ formation of CpFe-activated com-
plexes act-K (b).
est, both these approaches met limited success in terms of
Dibromide (R)-1 was converted into the more reactive
enantioselectivity (up to 31% ee in ketone AH and up to diiodide (R)-2, which was treated with [(trimethylsilyl)eth-
[
17]
2
5% ee in ketone asymmetric transfer hydrogenation, ynyl]magnesium bromide in the presence of CuI to yield
respectively).
the diyne (R)-3. The latter compound was then cyclized un-
[
12a]
der the conditions reported by Renaud et al.
[Fe (CO)9
2
in toluene at 90 °C] to yield the complex (R)-CK1, which
proved to be stable in air as expected, and could be purified
Results and Discussion
Our approach to the development of chiral K-type com- by chromatography.
plexes (CK) envisages the use of BINOL-derived chiral
cyclopentadienone ligands (Figure 2), whose design was in- catalytic systems
Considering the previously reported BINOL-derived
[
15,18]
and the commonly accepted mecha-
[
11b]
spired by the chiral Cp ligands recently reported by Cramer nism of the act-K-catalyzed reductions,
we envisioned
III
[15]
et al. for Rh catalysis.
that 3,3Ј-disubstitution on the binaphthyl moiety would be
The synthesis of the 3,3Ј-unsubstituted complex (R)-CK1 needed to ensure an efficient transfer of stereochemical in-
(
Scheme 1) was carried out in three steps starting from the formation from the catalyst’s stereoaxis to the substrate. In-
[16]
[11b]
commercially available compound (R)-1.
deed, in the commonly accepted transition state (TS)
Figure 2. General structure of chiral pre-catalysts CK (a) and the expected importance of 3,3Ј-disubstituted binaphthyls in AH (b).
Scheme 1. Synthesis of the pre-catalyst (R)-CK1.
2
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Chiral (Cyclopentadienone)iron Complexes
Scheme 2. Synthesis of the 3,3Ј-disubstituted pre-catalyst (R)-CK2.
Scheme 3. Synthesis of complex (R)-CK3 by demethylation of (R)-CK2.
[
see Figure 2 (b)], the substrate is located at a remarkable
distance from the cyclopentadienone-fused ring, where the
stereogenic unit of CK complexes is located. For this
reason, we decided to synthesize a 3,3Ј-disubstituted com-
plex as shown in Scheme 2.
The bis(bromomethyl) derivative (R)-4, prepared from
R)-BINOL as described by Maruoka et al.,[ was con-
16]
(
verted into the corresponding diiodide (R)-5, which was
then treated with [(trimethylsilyl)ethynyl]lithium to yield the
diyne (R)-6 in 80% yield.[ Remarkably, this double alk-
ynylation only proceeded in the presence of methoxy groups
in the 3,3Ј-positions, which prevented us from preparing
other 3,3Ј-disubstituted derivatives. Compound (R)-6 was
then cyclized in the presence of Fe (CO) to yield the 3,3Ј-
19]
2
9
dimethoxy-substituted pre-catalyst (R)-CK2. Attempts to
grow crystals of complexes CK1 and CK2 failed due to their
high solubility in the most common organic solvents. We
thus decided to convert CK2 into the corresponding 3,3Ј-
dihydroxy derivative CK3 (Scheme 3), as we expected the
latter to be easier to crystallize in apolar solvents. Quite
harsh reaction conditions (BBr with Bu NI as activator at
Figure 3. ORTEP diagram of the molecular structure of (R)-CK3
thermal ellipsoids set at the 50% probability level). Co-crystallized
solvent molecules are omitted for clarity.
(
3
4
[
20]
85 °C ) were necessary to achieve full deprotection.
Pre-catalysts CK1, CK2 and CK3 were initially tested in
Nevertheless, compound (R)-CK3 could be obtained in the AH of acetophenone S1 (Table 1, Entry 1–3) under the
good yield (80%), which confirmed the remarkable stability conditions described by Beller and co-workers,[
13]
i.e.
of the (cyclopentadienone)iron complex. employing K CO as activator to form the corresponding
2
3
To our delight, crystals suitable for X-ray diffraction complexes act-CK in situ [see Figure 1 (b)]. In each of the
analysis could be obtained by slow diffusion of hexane into three experiments a moderate conversion (54–68%) was ob-
a DCM solution of complex CK3[ (Figure 3).
21]
tained, along with enantioselectivity in favor of (S)-1-phen-
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L. Pignataro, U. Piarulli, C. Gennari et al.
SHORT COMMUNICATION
ylethanol (P1).[22] Very low conversions (Ͻ 5%) were ob- The most enantioselective pre-catalyst CK2 was selected for
served in the absence of H suggesting that the hydrogen- further optimization of the reaction parameters. First of all,
2
ation pathway is predominant over the transfer hydrogen- a series of different activators were screened (Table 1, En-
[
13a,23]
ation from iPrOH.
In agreement with our expecta- try 4–11): while K CO was confirmed to be the most ef-
2 3
tion, substitution at the 3,3Ј-positions of the binaphthyl ficient inorganic base in terms of conversion (Entry 2 vs.
moiety strongly affects the level of enantioselectivity: the Entries 4–10), the oxidative CO decomplexation with
[
12]
observed ee follows the same trend of the steric bulk of 3,3Ј- Me NO
turned out to be the most efficient activation
3
substituents: H (CK1, Entry 1) ϽϽ OH (CK3, Entry 3) Ͻ methodology, leading to high conversion (Entry 11).
OMe (CK2, Entry 2).
The optimization was continued by assessing the effect
of changing H pressure, temperature and solvent (Table 2).
2
Table 1. Test of CK pre-catalysts in the AH of acetophenone (S1) We found that neither increasing pressure (Entry 2) nor
and screening of different activators.[
a]
temperature (Entry 3) led to full conversion, which instead
could be obtained by increasing the catalyst loading to
2
mol-% (Entry 5; isolated yield 94%). Lowering the tem-
perature to 50 °C increased the ee to 55%, but at the cost
of conversion (Entry 4). We next screened several different
solvents (Entries 7–15), but all of them gave lower conver-
sions compared to the iPrOH/H O (5:2) mixture. In par-
ticular, the presence of water turned out to be beneficial for
the conversion (cf. Entries 1 and 7).
2
Entry
CK
Activator
Conversion [%][b]
ee [%][b,c]
1
2
3
CK1
CK2
CK3
K
2
K
2
K
2
CO
CO
CO
3
3
3
62
54
68
8
49
47
Having established the optimal reaction conditions for
the act-CK2-catalyzed AH, we assessed the scope of the re-
action (Table 3).
As expected, electron-poor acetophenone derivatives (S2
and S4) were more reactive than electron-rich 4Ј-methoxy-
acetophenone (S3) (Table 3, Entry 2 vs. Entries 1 and 3). As
a general trend for the methyl ketones (Table 3, Entries 1–6
and 11–13), S-selectivity was always observed, and the ee
increased along with the steric bulk of the other C=O sub-
4
5
6
7
8
9
CK2
CK2
CK2
CK2
CK2
CK2
CK2
CK2
Li
Na
Cs
LiOH
2
CO
CO
CO
3
9
52
53
51
51
50
52
53
50
2
3
25
29
49
35
30
23
84
2
3
NaOH
KOH
1
1
0
1
K
3
PO
4
Me NO
3
[
a] Reaction conditions: S1/CK/activator = 100:1:2, PH2 = 30 bar,
solvent = iPrOH/H O (5:2), c (S1) = 1.43 m, T = 70 °C, reaction
time 18 h. [b] Determined by GC with a chiral capillary column
MEGADEX DACTBSβ, diacetyl-tert-butylsilyl-β-cyclodextrin).
stituent (tBu Ͼ 1-Np Ͼ Cy Ͼ 2-Np ≈ Ph ≈ Py ≈ p-XC H4
6
2
0
ϾϾ iBu). Unfortunately, the most hindered substrates also
gave lower conversions (e.g., Table 3, Entries 4 and 13). The
(
[
c] Absolute configuration: S in all cases (assigned by comparison hydrogenation of 3-acetylpyridine (S7) also proved to be
[22]
of the optical rotation sign with literature data ).
sluggish (Table 3, Entry 6), possibly due to its ability to co-
ordinate Fe. A similar trend was observed for cyclic ketones,
Remarkably, the observed stereochemical preference for with 1-tetralone (S9) giving a much higher ee (77%) and a
S)-P1 is consistent with a pericyclic TS[
orients its larger substituent (Ph) away from the binaphthyl vs. 9). Surprisingly, the reduction of S10 and S11 showed
-substituent (OMe) to minimize steric clash (Figure 4). opposite stereochemical preference (R- instead of S-prod-
11b]
where S1 lower conversion than 2-tetralone (S10) (Table 3, Entry 8
(
3
Figure 4. Stereoselection model based on the commonly accepted TS of act-K-catalyzed AH.[11b]
4
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Chiral (Cyclopentadienone)iron Complexes
Table 2. Optimization of reaction parameters of the AH of acetophenone (S1) promoted by pre-catalyst CK2.[a]
Entry
Solvent
P [bar]
T [°C]
Conversion [%][b]
ee [%][b,c]
1
2
3
4
iPrOH/H
2
2
2
2
2
2
O (5:2)
30
50
30
30
30
30
70
70
80
50
70
70
84
85
59
33
100
58
50
51
50
55
50
51
iPrOH/H
iPrOH/H
iPrOH/H
iPrOH/H
iPrOH/H
O (5:2)
O (5:2)
O (5:2)
O (5:2)
O (5:2)
[
d]
[e]
5
[
f]
6
7
8
9
iPrOH
30
30
30
30
30
30
30
30
30
70
70
70
70
70
70
70
70
70
15
21
74
56
56
3
26
34
8
54
49
42
52
52
53
54
54
53
EtOH/H
2
O (5:2)
CF
3
CH
2
2
OH/H O (5:2)
1
0
1
2
3
4
5
DME/H
dioxane/H
CH CN/H
DMF/H O (5:2)
O (5:2)
O (5:2)
2
O (5:2)
O (5:2)
O (5:2)
1
1
1
1
1
2
3
2
2
DCE/H
2
toluene/H
2
[
a] Reaction conditions: S1/CK2/Me
3
NO = 100:1:2, PH2 = 30 bar, c
0
(S1) = 1.43 m. [b] See the footnote of Table 1. [c] See the footnote of
(S1) = 0.72 m.
Table 1. [d] 2 mol-% CK2 (4 mol-% Me
3
NO) employed. [e] Yield of the isolated product P1 94%. [f] c
0
uct). Propiophenone (S8) (Table 3, Entry 7) gave a similar to the mixtures. Each vial was capped with a Teflon septum pierced
by a needle, the block was transferred into the autoclave, and
stirring was started. After purging four times with hydrogen at the
selected pressure, heating was started. The reactions were stirred
under hydrogen pressure overnight and then analyzed for conver-
sion and ee determination.
conversion and a slightly better ee than acetophenone (S1)
(Table 2, Entry 4).
Conclusions
We have developed new BINOL-derived chiral (cyclo-
pentadienone)iron complexes (CK), which display high
stability to air, moisture and chromatography. The new
compounds can be converted in situ into the corresponding
Acknowledgments
We thank the European Commission [ITN-EID “REDUCTO”
PITN-GA-2012-316371] for financial support and for predoctoral
hydroxycyclopentadienyl complexes act-CK, which catalyze fellowships (to P. G. and M. R.-C.). L. P. thanks the Dipartimento
the AH of ketones with better enantioselectivities (up to di Chimica, Università di Milano, for financial support (Piano di
7
7% ee) than any other reported chiral (cyclopenta- sviluppo dell’Ateneo–anno 2014–Linea B.1–grants for young -
[5c,12d]
researchers).
dienone)iron complex.
As the obtained enantio-
selectivity increases with the steric bulk of the binaphthyl
3
,3Ј-substituents of CK, future work will focus on the syn- [1] For a comprehensive review of the topic, see: Handbook of
Homogeneous Hydrogenation (Eds.: J. G. de Vries, C. J. Elsev-
thesis of new complexes with various 3,3Ј-substituents start-
ing from the 3,3Ј-dihydroxy-substituted complex CK3.
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Experimental Section
[
General Procedure for the Asymmetric Hydrogenation: Hydrogen-
ations were run in a 450 mL Parr autoclave equipped with a remov-
able aluminum block that can accommodate up to fifteen magneti-
cally stirred 7 mL glass vials. The catalyst [0.005 mmol (1 mol-%) [4] For selected reviews covering Fe-catalyzed AH, see: a) K. Go-
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or 0.01 mmol (2 mol-%)] was weighed in the glass vials, which were
accommodated in the aluminum block after adding magnetic stir
bars in each of them. The block was placed in a Schlenk tube,
where it was subjected to three vacuum/nitrogen cycles. iPrOH
[
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(
0.25 mL) was added to each vial, and stirring was started. Me
0.01 mmol (2 mol-%) or 0.02 mmol (4 mol-%)] was added to each
vial as an H O solution (0.1 mL). After stirring at room tempera-
ture under nitrogen for 10 min, the substrate (0.5 mmol) was added
3
NO
[
2
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L. Pignataro, U. Piarulli, C. Gennari et al.
SHORT COMMUNICATION
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[
[
2
19] The reaction run under the conditions (copper catalysis)
adopted for preparing the 3,3Ј-unsubstituted compound (R)-3
did not show any conversion in this case.
[
a] Reaction conditions: substrate/CK2/Me
3
NO = 100:2:4, PH2
(substrate) = 1.43 m, T =
0 °C, reaction time 18 h. [b] Determined by GC with a chiral capil-
=
3
7
0 bar, solvent = iPrOH/H
2
O (5:2), c
0
[20] P. R. Brooks, M. C. Wirtz, M. G. Vetelino, D. M. Rescek, G. F.
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9719–9721.
[21] For full crystallographic data, selected distances/angles, and a
comparison with related complexes, see the Supporting Infor-
mation. CCDC-1037376 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
lary column (see the Supporting Information). [c] Determined by
GC or HPLC with a chiral capillary column (see the Supporting
Information). [d] Assigned by comparison of the sign of optical
rotation with literature data (see the Supporting Information).
[
3
e] Substrate/CK2/Me NO = 100:5:10.
6
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Job/Unit: O50146
/KAP1
Date: 12-02-15 14:36:48
Pages: 8
Chiral (Cyclopentadienone)iron Complexes
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[23] It is well known that (hydroxycyclopentadienyl)iron complexes
act-K (either pre-isolated or generated in situ) can also promote
[
22] For the absolute configuration assigned by comparison of the
sign of optical rotation with literature data, see: R. Patchett, I.
Magpantay, L. Saudan, C. Schotes, A. Mezzetti, F. Santoro,
Angew. Chem. Int. Ed. 2013, 52, 10352–10355; Angew. Chem.
ketone transfer hydrogenation and alcohol dehydrogenation
processes, see: a) Refs.[
8,11a,12d]
; b) S. A. Moyer, T. W. Funk,
Tetrahedron Lett. 2010, 51, 5430–5433.
Received: January 29, 2015
Published Online: ᭿
2013, 125, 10542–10545.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O50146
/KAP1
Date: 12-02-15 14:36:48
Pages: 8
L. Pignataro, U. Piarulli, C. Gennari et al.
SHORT COMMUNICATION
Iron Catalysis
P. Gajewski, M. Renom-Carrasco,
S. V. Facchini, L. Pignataro,* L. Lefort,
J. G. de Vries, R. Ferraccioli, A. Forni,
U. Piarulli,* C. Gennari* .................. 1–8
Chiral (Cyclopentadienone)iron Com-
plexes for the Catalytic Asymmetric Hydro-
genation of Ketones
Keywords: Asymmetric catalysis / Hydro-
genation / Chiral auxiliaries / Iron / Homo-
geneous catalysis / Ketones / Reduction
Reducto! Chiral (cyclopentadienone)iron
complexes were synthesized and tested,
after in situ activation, in the catalytic
asymmetric hydrogenation of ketones lead-
ing to the highest enantiomeric excesses
ever obtained with this type of catalysts.
8
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