Base-Free Asymmetric Transfer Hydrogenation of 1,2-Di- and Monoketones Catalyzed by a (NH)2P2-Macrocyclic Iron(II) Hydride

Article abstract of DOI:10.1002/anie.201706261

The hydride isonitrile complex [FeH(CNCEt₃)(1 a)]BF₄ (2) containing a chiral P₂(NH)₂ macrocycle (1 a), in the presence of 2-propanol as hydrogen donor, catalyzes the base-free asymmetric transfer hydrogenation (ATH) of prostereogenic ketones to alcohols and the hemihydrogenation of benzils to benzoins, which contain a base-labile stereocenter. Benzoins are formed in up to 83 % isolated yield with enantioselectivity reaching 95 % ee. Ketones give the same enantioselectivity observed with the parent catalytic system [Fe(CNCEt₃)₂(1 a)] (3 a) that operates with added NaO^tBu.

Full text of DOI:10.1002/anie.201706261

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Accepted Article
Title: Base-Free Asymmetric Transfer Hydrogenation of 1,2-Di- and
Monoketones Catalyzed by a (NH)2P2-Macrocyclic FeII Hydride
Authors: Lorena De Luca and Antonio Mezzetti
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706261
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10.1002/anie.201706261
Angewandte Chemie International Edition
COMMUNICATION
Base-Free Asymmetric Transfer Hydrogenation of 1,2-Di- and
Monoketones Catalyzed by a (NH)2P2-Macrocyclic FeII Hydride**
Lorena De Luca and Antonio Mezzetti*
Abstract: The hydride isonitrile complex [FeH(CNCEt3)(1a)]BF4 (2)
containing a chiral P2(NH)2 macrocycle (1a), in the presence of 2-
propanol as hydrogen donor, catalyzes the base-free asymmetric
transfer hydrogenation (ATH) of prostereogenic ketones to alcohols
and the hemihydrogenation of benzils to benzoins, which contain a
base-labile stereocenter. Benzoins are formed in up to 83% isolated
yield with enantioselectivity reaching 95% ee. Ketones give the
same enantioselectivity observed with the parent catalytic system
[Fe(CNCEt3)2(1a)] (3a) that operates with added NaOtBu.
reactions,[16]
enzymatic
reductions,[17]
and
asymmetric
hydrosilylation with chiral frustrated Leiws pairs.[18] Enantiopure
propargylic alcohols can be converted to O-acylated α-
hydroxyketones without racemization/epimerization.[19] However,
most of the above methods have drawbacks in terms of catalyst
loading, substrate scope, enantioselectivity, or atom economy,
which might be overcome by an approach based on asymmetric
hydrogenation. After Ohgo's pioneering cobalt-catalyzed H2
hydrogenation of benzil to benzoin with modest enan-
tioselectivity (62% ee),[20] advances have been slow. Asymmetric
transfer hydrogenation (ATH) has been used to reduce 1-
phenyl-1,2-propanedione to the enantiopure α-hydroxy ketone B
(Chart 1).[5a] To the best of our knowledge, however, no highly
enantioselective hydrogenation catalyst has been reported for
the hydrogenation of benzils to benzoins (A).
Asymmetric transfer hydrogenation (ATH) is experiencing a
golden age[1] also thanks to the development of earth-abundant,
nontoxic catalysts of base metals.[2] However, the base additives
that are required to activate the precatalyst[3] tend to limit the
reaction scope. An eminent example are α-hydroxy ketones, e.g.
benzoin (A) or, more generically, acyloins (Chart 1), whose
base-labile stereocenter easily racemizes upon heating or in
basic media,[4] making the asymmetric hemihydrogenation of
1,2-diketones a formidable challenge.[5]
Therefore, we set out to develop a catalyst for the asymme-
tric hydrogenation of base-sensitve carbonyl compounds, in
particular benzil, starting from our recently reported bis(isonitrile)
iron(II) complexes [Fe(CNR)2(1)](BF4)2 (3) containing the chiral
(NH)2P2 macrocycles 1a and 1b (Chart 2), which catalyze the
ATH of a broad spectrum of ketones upon activation with
NaOtBu.[21]
OH
OH
O
O
A
B
H
(BF4)2
N
Chart 1. Acycloins (such as A and B) contain a base-labile stereocenter.
(S)
(S)
Ph
P
C
N
C
H
NH HN
Fe
P
N
N
(S) (S)
Et3C
CEt3
P
P
Enantiomerically pure acyloins are frequent structural
subunits in natural products[6] and bioactive molecules,[7] and act
as chiral templates and building blocks[8] thanks to the
combination of the highly directing hydroxyl group with the easily
functionalized prostereogenic carbonyl.[9] Their synthesis has
been accomplished by a number of chemical and biocatalytic[7]
methods such as the stoichiometric[10] and catalytic[11] oxidation
of enolates or enol ethers, alkene ketohydroxylation,[9] oxidative
kinetic resolution,[12] dynamic kinetic resolution,[13] monooxidation
of 1,2-diols,[14] benzoin condensation,[15] Friedel-Crafts
n
Ph
Ph
n = 2, 3a Ph
n = 1, 3b
n
n = 2, 1a; n = 1, 1b
Chart 2. Macrocyclic iron(II)/(NH)2P2 complexes
The base-free ATH of carbonyl functions has been
pioneered with iridium,[22] and several achiral catalysts have
been reported.[23] Yet, the base issue does not affect only
transfer hydrogenation,[1,3] as also catalysts for the direct (H2)
hydrogenation (AH) of ketones require basic activation. In the
case of iron(II), achiral BH4 adducts catalyze the H2 hydro-
genation of ketones without the addition of base.[24] However,
[*]
M. Sc. L. De Luca, Prof. Dr. A. Mezzetti
Departement Chemie und Angewandte Biowissenschaften
Eidgenössische Technische Hochschule (ETH) Zürich
8093 Zürich (Switzerland)
–
due to the formation of alkoxide from BH4 in the alcoholic
medium, this system may be unsuitable for base-sensitive
substrates.
A notable exception is Noyori's base-free AH
E-mail: mezzetti@inorg.chem.ethz.ch
ruthenium(II) catalyst, which, however, as not been tested with
1,2-diphenylethane-1,2-diones (benzils).[25] We report here the
first base-free FeII catalyst for the ATH of ketones, the hydride
complex [FeH(CNR)(1a)]BF4 (2), which promotes the asymme-
[**]
We thank Prof. Dr. Kilian Muñiz for the useful discussion and the
ETH Zürich for financial support to L. D. L. (grant no. ETH-0914-2).
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706261
Angewandte Chemie International Edition
COMMUNICATION
tric hemireduction of benzils to the corresponding benzoins with
up to 95% ee, and of monoketones with up to 99% ee.
donor to benchmark it against the base-activated precatalyst
[Fe(CNR)2(1a)](BF4)2 (3a).[21a] Therefore, the same substrate
amount, concentration, and catalyst loading were used. Beside
the absence of base, the only difference was the small amount
of THF deriving from the preparation of 2. In fact, the hydride
complex 2 was prepared before each catalytic run by treating 5
with NaBHEt3 (1 equiv) in THF (0.4 mL) at room temperature.
After stirring for 5 min, the solution was diluted with 2-propanol
(12.5 mL) and heated to 50°C. After stirring for 10 min, the
reaction was started by adding one of the ketones 6 (2.5 mmol).
The resulting light orange solution was stirred at 50°C and
sampled at regular intervals to determine the conversion to the
corresponding alcohols (R)-7 and the enantioselectivity (by
chiral GC or HPLC depending on the substrate). The reaction
times reported in Table 1 are those at which the ATH reaction
has just reached equilibrium.
Hydride 2 was prepared stepwise from [Fe(MeCN)2(1a)]
(4a)[21f] by reaction with CNCEt3 (1 equiv) and an excess of KBr
in dichloromethane at 50°C for 16 h (Scheme 1). The resulting
bromoisonitrile complex trans-[FeBr(CNCEt3)]BF4 (5) was
isolated as orange solid after filtering off the salts and precipita-
tion with hexane (80% yield, see Supporting Information).[26] The
inequivalent P atoms give a tight AX system in the 31P{1H} NMR
2
spectrum (δ 54.3 and 49.0, JP,P’=59.5 Hz, THF-d8), suggesting
that both phosphines are trans to amine. The trans configuration
2
is further supported by the similar JP,C coupling constants (27.9
and 23.0 Hz) observed in the 31P{1H} NMR spectrum of the 13C-
labeled isonitrile derivative [FeBr(13CNCEt3)(1a)]BF4 (5'), which
shows that the isonitrile ligand is cis to both phosphines.
BF4
(BF4)2
H
N
OH
OH
OH
OH
F3C
H
H
MeO
CNCEt3
(1 equiv)
Br
Fe
L
N
P
N
P
Ph
P
N
N
H
(R)-7a
(R)-7b
(R)-7c
(R)-7d
Fe
P
N
CF3
KBr (excess)
CH2Cl2
Ph
Ph
Ph
Chart 3. Scope of the ATH of ketones
5 (L = CNCEt3)
4
Scheme 1. Synthesis of bromoisonitrile complex 5
With acetophenone (6a), the hydride complex 2 is less active
than the previously reported, closely related system that uses
the bis(isonitrile) complex 3a and NaOtBu as added base (Table
1, entries 1, 3). However, the enantioselectivity is the same
(98% ee). When base (NaOtBu, 1 mol%) is added to the reaction
catalyzed by hydride 2, acetophenone is reduced at the same
rate observed with 3a/NaOtBu, indicating that the base plays a
role in catalytic turnover, while the enantioselectivity is slightly
improved.
The bromoisonitrile complex 5 reacts with NaBHEt3 (1 equiv)
in THF to give cis-β-[FeH(CNCEt3)(1a)]BF4 (2) (Scheme 2).
BF4
BF4
H
N
H
H
NaBHEt3
(1 equiv)
Br
Fe
L
N
P
N
P
Ph
P
H
N
C
H
Fe
P
Table 1. Asymmetric Transfer Hydrogenation of 6 to 7 with 2 and 3a.a
THF
N
CEt3
entry[a]
Substr.
Cat.
Ph
Ph
Base
(mol%)
t
TOF[b]
(h–1
Yield
(%)
ee
(%)
Ph
(h)
)
5 (L = CNCEt3)
2
1
2
3
4
5
6
7
8
9
6a
6a
6a
6b
6b
6c
6c
6d
6d
2
2
0
1
1
0
1
0
1
0
1
1.0
0.5
1885
3013
3426
3209
8580
3457
9430
4690
8160
92
90
98
99
98
98
97
98
99
64
68
Scheme 2. Synthesis of hydride complex 2
3a
2
0.5
93
Hydride 2 decomposes upon isolation, but is stable in THF
solution under argon for at least 15 days and was characterized
in solution. In the 1H NMR spectrum in THF-d8, the hydride
ligand gives a doublet of doublets at δ –5.45 with similar
coupling constants (2JP,H=64.6 Hz, 2JP’,H=57.5 Hz), indicating that
it is cis to both phosphines. In the 31P{1H} NMR spectrum, the
high-frequency shift of one of the AX signals (δ 65.5 and 37.7,
2JP,P’=27.6 Hz) suggests that one phosphine is trans to isonitrile.
Accordingly, in the 31P{1H} NMR spectrum of the 13C-labeled
analogue, the P,C-coupling constants to the isonitrile ligand
differ widely between the phosphine resonating at δ 65.5
(2JP,C=27.0 Hz) and the one at δ 37.7 (2JP,C=14.6 Hz).
1.5
93
3a
2
0.5
92
0.2
quant
quant
81
3a
2
0.5
0.25
0.25
3a
82
[a] Reaction conditions: Substrate 6 (2.5 mmol), catalyst 2 or 3a (2.5 µmol,
0.1 mol%), 2-propanol, T=50°C. Results with catalyst 3a were obtained with
added NaOtBu (0.025 mmol, 1 mol%) (data from ref. 21a). Conversion and
enantiomeric excess were determined by GC and HPLC, respectively (see
Supporting Information for details). [b] TOF at 15 min.
The hydride complex cis-β-[FeH(CNCEt3)(1a)]BF4 (2) was
tested in the base-free asymmetric transfer hydrogenation of
standard substrates (Chart 3) with 2-propanol as hydrogen
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10.1002/anie.201706261
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COMMUNICATION
F
OMe
The reaction of the electron-rich 6b is significantly slower
with catalyst 2 than with 3a/NaOtBu, but the enantioselectivity
reaches 98% ee at reaction completeness (entries 4, 5).
Interestingly, the industrially relevant, electron-poor 6c was
converted quantitatively in a shorter time (15 min) with catalyst 2
than with 3a (30 min, entries 6, 7), albeit at the cost of marginally
lower enantioselectivity (98 and 99% ee, respectively). Both
catalysts reduce benzylideneacetone (6d) chemoselectively at
the carbonyl function with comparable enantioselectivity (64 and
68% ee, entries 8, 9).
OH
OH
OH
O
O
O
F
MeO
9a
9b
9c
F
OH
OH
OH
F
MeO
F
OMe
O
F
O
9d
O
9e
9f
Br
Cl OH
OH
O
Cl
O
Br
9g
9h
Then, to take advantage of the base-free nature of ATH
catalyzed by hydride 2, benzils (8) were studied as substrates,
as their hemireduction gives α-hydroxyketones (Scheme 3),
which undergo rapid stereomutation in the presence of base.[4]
Preliminary experiments showed that 1,2-diphenylethane-1,2-
dione (8a) is reduced sluggishly to benzoin (9a) under the
conditions used for ketones 6 (Scheme 3, Table 1). However,
upon increasing the catalyst loading to 1 mol% and lowering the
substrate concentration to 0.05 M, benzoin (9a) was obtained
with 75% yield and 95% ee after 75 min (Table 2, entry 1). Only
traces of hydrobenzoin (10a) were detected after this reaction
Chart 4. Scope of the base-free ATH of 1,2-diketones 8 to benzoins (S)-9.
The para-substituted benzils 8b and 8c gave the cor-
responding benzoins 9b and 9c with high yields and good
enantioselectivity regardless of the electronic properties of the
substituents. The bromo analogue 8h apparently deviates from
this trend as it gives only 56% ee, probably because of its poor
i
solubility (the reaction was never homogeneous in PrOH at
50 °C). Instead, the meta-substituted analogues are sensitive to
electronic factors. Thus, 1,2-bis(3-methoxyphenyl)ethane-1,2-
dione (8d) gave the corresponding α-hydroxyketone 9d in good
yield (67%) and high enantioselectivity (87% ee) after 2 h of
reaction time, whereas the reduction of its fluoro analogue 8e
proceeded faster, but at the price of a lower enantioselectivity
(49% ee). The ortho substituted 1,2-bis(2-fluorophenyl)ethane-
1,2-dione (8f) gave benzoin 9f with lower yield and with 62% ee,
whereas bulkier ortho substituents such as in 8g significantly
decrease the enantioselectivity (41% ee).
i
time. Recrystallization from PrOH gave (S)-benzoin (9a) as a
single enantiomer (ee > 99.95%) with 61% overall yield.
OH
R
(S)
2
O
R
R
R
(S)-9a-9h
(1 mol%)
O
+
R
iPrOH
50 °C
O
OH
R
(R)
8a-8h
(0.05 M )
Table 2. Asymmetric Transfer Hydrogenation with
2 under Base-free
(S)
conditionsa
10a-10h
(traces)
OH
entry[a]
Substr.
t
Yield of 9
ee of 9
(min)
(%)
(%)
Scheme 3. ATH of benzils with catalyst 2
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
75
90
45
120
60
30
75
45
70 (61)
73 (65)
83
95 (>99.95)b
84 (93) b
89
For the sake of comparison, 8a was hydrogenated with
catalyst 3a in the presence of base (NaOtBu, 10 equiv). After a
reaction time of 15 min, racemic benzoin (9a) was formed (22%)
along with a conspicuous amount of meso-hydrobenzoin (10a)
(54% GC yield). After 30 min of reaction time, benzil conversion
to (R,S)-10a was quantitative (by GC). Thus, the base strongly
accelerates the ATH reaction as expected,[3,27] and the second
hydrogenation step occurs under substrate control (see
Supporting Information).[28]
55
87
58
49
39
62
8g
8h
51
41
56
56
The excellent and unprecedented result achieved with 8a
prompted us to broaden the scope to the substituted benzoins
9b-9h in Chart 4. The reaction times were optimized for each
substrate 8a-8h by monitoring the ATH reaction by GC in
preliminary runs, after which the reaction was repeated and
stopped just before the appearance of hydrobenzoins 10a-10h.
The isolated yields and ee values of benzoins 9a-9h are given in
Table 2. The enantiopurity of 9a and 9b was enhanced by
recrystallization, whereas 9c-9h recrystallized only on standing
and hence without enantioenrichment. The absolute configura-
tion of 9a-9h was determined to be S by the sign of the optical
rotation (see Supporting Information).
[a] Reaction conditions: Substrate (0.625 mmol), catalyst 2 (6.25 µmol, 1
mol%), 2-propanol 0.05 M, T=50°C. Yields are isolated, data in parentheses
are after recrystallization. The enantiomeric excess was determined by chiral
HPLC (see Supporting Information for details). [b] After single recrystallization
from hot iPrOH.
The lability of the stereocenter of benzoins 9 in the presence
of base has been exploited in highly enantioselective dynamic
kinetic resolution (DKR) of benzils to hydrobenzoins for the
enantioselective transfer hydrogenation of benzil 8a to hydro-
benzoin 10a with HCOOH/NEt3 catalyzed by [RuCl(Tsdpen)(η6-
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10.1002/anie.201706261
Angewandte Chemie International Edition
COMMUNICATION
arene)].[4] However, to the best of our knowledge, hydride 2 is
the first example of catalyst for the asymmetric hemihydro-
genation of benzils to benzoins. The use of a hydride complex
such 2, which neither needs base activation nor releases an
internal base during the reaction, is pivotal in order to perform
the asymmetric transfer hydrogenation of base-sensitive
substrates. Although mechanistic speculations are beyond the
scope of this paper, the similar performance of 2 and 3a/NaOtBu,
in particular after addition of base to hydride 2, is striking and
may hint to the involvement of hydride 2, or of a closely related
species, in the catalytic cycle with both systems. A mechanistic
investigation is under way, and its results will be reported in due
time.
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Keywords: Acyloins • Iron • Base-free • Asymmetric transfer
hydrogenation• Macrocyclic ligands
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10.1002/anie.201706261
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
M. Sc. L. De Luca, Prof. Dr. A. Mezzetti*
Page No. – Page No.
Base-Free Asymmetric Transfer
Hydrogenation of 1,2-Di- and
Monoketones Catalyzed by a (NH)2P2-
Macrocyclic FeII Hydride
Base? No Thanks! A hydride isonitrile iron(II) complex bearing a C2-symmetric di-
amino (NH)2P2 macrocyclic ligand catalyzes the asymmetric transfer hydrogenation
of ketones under base-free conditions with excellent enantioselectivity (up to 99%
ee). Base-labile benzoins are formed from the corresponding benzils with up to
95% ee.
This article is protected by copyright. All rights reserved.