RETRACTED ARTICLE: The Manganese(I)-Catalyzed Asymmetric Transfer Hydrogenation of Ketones: Disclosing the Macrocylic Privilege

Article abstract of DOI:10.1002/anie.201912605

The bis(carbonyl) manganese(I) complex [Mn(CO)₂(1)]Br (2) with a chiral (NH)₂P₂ macrocyclic ligand (1) catalyzes the asymmetric transfer hydrogenation of polar double bonds with 2-propanol as the hydrogen source. Ketones (43 substrates) are reduced to alcohols in high yields (up to >99 %) and with excellent enantioselectivities (90–99 % ee). A stereochemical model based on attractive CH–π interactions is proposed.

Full text of DOI:10.1002/anie.201912605

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Accepted Article
Title: The Manganese(I)-Catalyzed Asymmetric Transfer
Hydrogenation of Ketones: Disclosing the Macrocyclic Privilege
Authors: Alessandro Passera and Antonio Mezzetti
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912605
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10.1002/anie.201912605
Angewandte Chemie International Edition
COMMUNICATION
The Manganese(I)-Catalyzed Asymmetric Transfer Hydrogenation
of Ketones: Disclosing the Macrocylic Privilege
Alessandro Passera[a] and Antonio Mezzetti*[a]
Abstract: The bis(carbonyl) manganese(I) complex [Mn(CO)2(1)]Br
(2) with a chiral (NH)2P2 macrocyclic ligand (1) catalyzes the asym-
metric transfer hydrogenation (ATH) of polar double bonds with 2-
propanol as hydrogen source. Ketones (43 substrates) are reduced
to alcohols in high yield (up to >99%), and excellent enantioselec-
tivity (90–99% ee). A stereochemical model based on attractive
CH/π interactions is proposed.
transfer hydrogenation of a broad number of substrates (43) with
enantioselectivity ranging from 90 to 99% ee that is based on
the previously developed chiral (NH)2P2 macrocycle 1 (Scheme
1).[5] Catalyst 2 outperforms both C and the asymmetric transfer
hydrogenation catalysts E and F, which give low to moderate
enantioselectivity (20–85 ee%) with aryl alkyl ketones.[23,24]
H
N
Br
In the last decade, the effort directed at replacing catalysts
based on precious metals with cheap and non-toxic first-row
transition metals[1] has mainly involved iron. Driven by the im-
portance of enantiopure alcohols,[2] iron catalysts have been
developed for the asymmetric hydrogenation of polar double
bonds.[3–7] In contrast, manganese has remained unexplored
(S)
(S)
[MnBr(CO)5]
NH HN
Ph
P
N
H
Mn
(S)
(S)
toluene
80 °C
CO
OC
P
P
P
Ph
Ph
Ph
1
2
until 2016, when it was applied in the non-enantioselective
[8–15]
Scheme 1. Synthesis of bis(carbonyl) complex [Mn(CO)2(1)]Br (2).
hydrogenation of polar multiple bonds with H2
and, more
rarely, under hydrogen transfer conditions.[16–18] Similarly,
enantioselective Mn(I) catalysts for ketone hydrogenation with
H2 (Clarke’s A,[19] Beller’s B,[20] Han’s and Ding’s C,[21] and our
D[22]) are more numerous than those for asymmetric transfer
hydrogenation (E[23] and F[24]) (Figure 1).[25] In particular, C
reduces alkyl aryl, diaryl, and cyclic ketones with high
enantioselectivity (85–98 ee%) in direct hydrogenation.[21]
The reaction of the chiral (NH)2P2 macrocyclic ligand 1 with
[MnBr(CO)5] in toluene for 3 h at 80 °C gives the bis(carbonyl)
Mn(I) complex [Mn(CO)2(1)]Br (2), which was precipitated with
hexane as a yellow powder (79% yield, Scheme 1). The 31P{1H}
NMR spectrum (AX, δ 58.7, 31.6, 2JP,P’= 51.0 Hz)[26] suggests the
presence of a single cis-β isomer with two cis CO ligands (1942,
1850 cm–1).[27]
Br
Br
Complex 2 catalyzes the asymmetric transfer hydrogenation
of acetophenone (3a) from 2-propanol in the presence of base.
An induction period was observed for the reaction, which was
suppressed by preactivating the catalyst (2) with base (2 h at
50 °C in 2-propanol, see Supporting Information). Most probably,
the deprotonation of one N–H group by base triggers the
dissociation of a CO ligand and forms an amido complex that is
the entry of the catalytic cycle, as suggested for other Mn(I)
catalysts.[22] No hydrogenation occurs in the absence of base.
Under optimized conditions (catalyst loading 2 mol%, 10
mol% NaOtBu, 50 °C, Table S1), acetophenone (0.2 M) was
reduced to 1-phenylethanol in 97% yield and with 94% ee after 3
h (Scheme 2). The enantioselectivity remains constant during
the reaction, and a poisoning test[3d,28] supports a homogenous
mechanism (Table S1).
Ph
N
P
P
N
Ph
CO
Br
N
H
CO
CO
H
N
CO
Mn CO
tBu
Mn CO
Mn
P
CO
CO
Fe
Ph2
P
NH
Clarke
(A)
iPr
Han and Ding
(C)
Beller
(B)
Me
Br
tBu
Ph
P
NH2
HBH3
Mn CO
Ph
Ph
N
CO
Br
H
N
Mn CO
Fe
H
N
OC
PPh2
Morris
(F)
P
Mn
PPh2
CO
iPr2
CO
P
CO
Me
tBu
our group
Zirakzadeh and Kirchner
(D)
(E)
Figure 1. Mn(I) catalysts for the asymmetric hydrogenation of ketones.
A broad scope of aryl alkyl ketones (Schemes 2–4) was
reduced to the secondary alcohols with yields up to >99% and
excellent enantioselectivity (90–99% ee). With acetophenones
(Scheme 2), catalyst 2 tolerates ortho, meta, and para substitu-
tion. The methyl- (3b–3d), methoxy- (3e–3g), and chloro- (3i–
3m) substituted substrates gave excellent enantioselectivity (up
to 99% ee). The catalyst is less active with ortho-substituted
substrates (3b, 3e, 3i), probably due to steric effects, but
increasing the reaction time from 3 to 6 h gives good yields (88–
98% yield). Notably, the 2,6-methoxy-disubstituted ketone 3h is
reduced at 80 °C within 9 h with 61% yield and 97% ee, which is
unprecedented with Mn(I).[19–25]
Herein, we report the most effective Mn(I) catalyst for the
[a]
A. Passera, Prof. Dr. A. Mezzetti
Departement Chemie und Angewandte Biowissenschaften
Eidgenössische Technische Hochschule (ETH) Zürich
8093 Zürich (Switzerland)
E-mail: mezzetti@inorg.chem.ethz.ch
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/anie.201912605
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COMMUNICATION
Analogously, 1-acetylpyrene (5c) was reduced in 6 h in 90%
yield and with 94% ee. Other aryl substituents (5d–5f) also give
good enantioselectivity (93% ee). This is the first asymmetric
Mn(I)-catalyzed hydrogenation of ketones containing large aryl
groups such as 1-acetylpyrene.[19–25]
H
N
Br
2 (2 mol%)
O
OH
NaOtBu
(10 mol%)
Ph
P
N
H
Mn
CO
OC
3
(R)-4
yield up to >99%
2-propanol
50 °C
R
R
P
(0.2 M)
90
–
99% ee
Ph
2
Br
H
N
O
Me
O
O
O
OMe O
2 (2 mol%)
NaOtBu
Me
OH
O
(10 mol%)
Ph
P
N
H
Mn
3a
3b
3c
94% (3 h)
90% ee
3d
3e
Me
Ar(Het)
Ar(Het)
CO
OC
97% (3 h) 89% (6 h)
93% (3 h) 88% (6 h)
94% ee 99% ee
OMe O Cl O
5
(R)-6
yield up to >99%
2-propanol
50 °C
P
94% ee
94% ee
(0.2 M)
O
O
93
–
98% ee
Ph
2
MeO
O
O
O
MeO
OMe
3ha
61% (9 h)
97% ee
O
3f
3g
90% (3 h)
96% ee
3i
95% (3 h)
97% ee
O
98% (6 h)
92% ee
5a
5b
5ca
90% (6 h)
94% ee
O
92% (3 h)
93% ee
O
90% (6 h)
96% ee
O
O
O
Cl
O
O
3j
3k
97% (3 h)
94% ee
3l
3m
97% (3 h)
95% ee
O
Cl
F
Br
97% (3 h)
96% ee
O
98% (3 h)
97% ee
5ea
91% (3 h)
93% ee
5d
93% (3 h)
93% ee
5f
91% (3 h)
93% ee
O
O
O
F3C
F3C
O
O
O
S
O
N
3n
98% (3 h)
90% ee
O
3o
99% (3 h)
97% ee
3p
3q
97% (3 h)
92% ee
I
F3CO
S
>99% (3 h)
98% ee
CF3
O
5g
71% (3 h)
97% ee
5h
83% (3 h)
98% ee
5i
5j
89% (3 h)
97% ee
>99% (2 h)
96% ee
O
Me2N
O
O
O
O
3r
3s
3t
>99% (3 h)
91% ee
O
Me2N
N
94% (3 h)
96% ee
96% (3 h)
90% ee
O
N
O
N
N
5k
94% (3 h)
93% ee
5l
5m
85% (5 h)
96% ee
5n
O
Fe
88% (5 h)
95% ee
90% (3 h)
97% ee
O
S
3wb
93% (3 h)
91% ee
N
3u
92% (3 h)
90% ee
3v
Me
Ph
O
91% (3 h)
93% ee
Scheme 3. Asymmetric transfer hydrogenation of heteroaromatic ketones.
Reaction conditions: substrate (0.5 mmol) in 2-propanol (2.5 mL, 0.2 M), 2 (2
mol%), NaOtBu (10 mol%), 50 °C. When the ketone was not soluble (5c and
5e), toluene (0.25 mL) was added. Reaction times are reported in parentheses.
Yields (%) and enantioselectivities (ee%) were determined by GC and chiral
HPLC or GC, respectively. a The yield (%) was determined by 1H NMR.
N
Scheme 2. Asymmetric transfer hydrogenation of substituted acetophenones.
Reaction conditions: substrate (0.5 mmol, 0.2 M in 2-propanol, 2.5 mL), 2 (2
mol%), NaOtBu (10 mol%), 50 °C. Reaction times are in parentheses. Yields
(%) and enantioselectivities (ee%) were determined by GC and chiral HPLC or
a
b
GC, respectively. At 80 °C. The ee was determined by 19F NMR spectro-
scopy after derivatization with enantiomerically pure (S)-Mosher’s acid chloride.
Several acyl-substituted heterocycles such as acetyl-
thiophenes (5g–5h), furan (5i), pyrrole (5j), indole (5k), and
pyridines (5l–5m) were reduced to the corresponding alcohols
without catalyst poisoning. Acetylthiophenes 5g and 5h are
reduced with 97–98% ee, but with lower conversions (64–77%)
as the electron-rich heterocycle stabilizes the ketone with
respect to the alcohol as confirmed by DFT (Scheme S1).
Accordingly, longer reaction times did not give higher yields.
Instead, 2-acetyl-N-methylpyrrole (5j) is quantitatively reduced in
2 h, its reaction being strongly exergonic as compared to
acetophenone (3a, Schemes 2 and S1). Acetyl pyridines 5l and
5m require longer reaction times (5 instead of 3 h as for 3a), but
give excellent 95–96% ee. Overall, all the acyl-substituted
heteroaromatics 5g–5m gave high enantioselectivity (93–98%
ee). Finally, acetyl ferrocene (5n) was hydrogenated with 90%
yield and 97% ee.
Besides alkyl and alkoxy, also halogen substituents (3i–3n)
are tolerated (90–97% ee). Also, 2 hydrogenates trifluoromethyl-
and trifluoromethoxy-subsituted ketones (3o–3q) with up to 98%
ee. Notably, 4o and 4p are important precursors for agricultural
fungicides[29] and NK1 receptor antagonists as Aprepitant,[30]
respectively. Also tertiary amines (3r–3u) are well tolerated (90–
96% ee). Complex 2 is the first chiral Mn(I) catalyst that hydro-
genates acetylanilines 3r–3s and 4’-(imidazol-1-yl)aceto-
phenone (3u).[19–25] Ketones are reduced chemoselectively in
the presence of C≡C triple bonds (3v) and sulfone (3w).
Polyaromatic methyl ketones such as 1- and 2-acetonaph-
thones (5a and 5b) give 93 and 96% ee, respectively (Scheme
3). The ortho-substituted 1-acetonaphthone (5b) requires a
longer reaction time than 5a (6 and 3 h, respectively), as with
ortho substituted acetophenones (3b, 3e, and 3i in Scheme 2).
Catalyst 2 tolerates bulky alkyl substituents such as in 7b–7f
(Scheme 4). Good yields (88–97%) are obtained at longer
2
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10.1002/anie.201912605
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COMMUNICATION
reaction times (up to 6 h for 7e) with high enantioselectivity (90–
97% ee). Benzaldehyde (7a) is reduced quantitatively in 2 h,
whereas propyl benzoate (7g) was not hydrogenated, and hence
the catalyst is chemoselective for ketones and aldehydes.
The enantioselectivity was rationalized by DFT[34] on the
enantiodetermining hydride/proton transfer step[20,22] assuming a
Noyori bifunctional mechanism[35] in which acetophenone forms
a hydrogen bond to the N–H group of the ligand (Figure 2). The
sense of induction and the calculated enantioselectivity are in
fair agreement with experiment (R, 99 vs 94% ee, respectively).
Br
2 (2 mol%)
NaOtBu
H
N
O
OH
(10 mol%)
R
R
Ph
P
N
H
Mn
CO
OC
2-propanol
50 °C
7
(R)-8
yield up to >99%
P
(0.2 M)
90–97% ee
2
Ph
O
O
O
O
H
7a
3a
7b
7c
>99% (2 h)
97% (3 h),
94% ee
O
93% (3 h),
97% ee
O
94% (4 h),
95% ee
O
O
10
OEt
7e
7f
7g
0% (6 h)
7d
97% (3 h),
90% ee
Figure 2. Diastereoisomeric hydride/proton transfer transition states. Relative
) are reported in parentheses. CH/π
interactions are depicted in black dashed lines.
Gibbs free energies (in kcal mol–1
85% (6 h),
93% ee
91% (3 h),
95% ee
Scheme 4. Asymmetric transfer hydrogenation of phenyl alkyl ketones.
Reaction conditions: substrate (0.5 mmol) in 2-propanol (2.5 mL, 0.2 M), 2 (2
mol%), NaOtBu (10 mol%), 50 °C. Reaction times are reported in parentheses.
Yields (%) and enantioselectivities (ee%) were determined by GC and chiral
HPLC or GC, respectively.
The Activation Strain Model (ASM)[36] suggests that ΔΔG0
between the two transition states strongly depends on the
interactions between the catalyst and the substrate (Table S4)
and is slightly influenced by the distortion of catalyst and sub-
strate upon approach. The analysis of non-covalent interactions
(NCI, Figures S144, S145)[37] in the most stable diastereoiso-
meric transition state TS(R) reveals attractive CH/π interactions
between the methyl group of acetophenone and the phosphine
phenyl ring (CH/π a, TS(R), Figure 2) that are missing in TS(S).
Additionally, the acetophenone phenyl gives attractive
interactions with N–CH protons of the ligand (CH/π b, TS(R),
Figure 2).
Our previous studies have shown that the bulky isonitrile in
the iron(II) analogue [Fe(CNCEt3)2(1)](BF4)2 is beneficial to
enantioselectivity.[5d,f,38] The present DFT study reveals that
attractive CH/π interactions between the substrate and macro-
cycle 1 induce high enantioselectivity (≥90% ee) even without
the assistance of bulky ancillary ligands and explain why aryl
alkyl ketones are the substrates of choice.
The only limitation for catalyst 2 is that the ketone must
contain at least one aromatic substituent. Thus, cyclohexyl
methyl ketone (7h) is not hydrogenated, and the DFT cal-
culations indicate that the activation barrier for hydride transfer is
4.2 kcal mol–1 higher than with acetophenone (Table S3).
In view of the high versatility of catalyst 2 and of its high
functional group tolerance, we studied haloperidol (9), an anta-
gonist of dopamine D2 receptor and antipsychotic drug,[31] which
is reduced to 10 during metabolism (Scheme 5).[31] Both 10 and
its derivatives are prospective anticancer drugs.[32] Catalyst 2
reduces haloperidol with 97% ee and 85% isolated yield on a
gram scale (Scheme 5). To best of our knowledge, this is the
first catalytic synthesis of enantiomerically pure 10, which is still
prepared by stoichiometric reduction of 9 with chiral boranes.[33]
Therefore, the (NH)2P2 macrocycles can be considered as
privileged ligands of their own, and their application to Mn(I)
leads to a further breakthrough in the asymmetric transfer hydro-
genation with base metal catalysts. In fact, the macrocyclic
catalyst 2 shows a significantly broader substrate scope and
enantioselectivity than H2 and transfer hydrogenation catalysts
of manganese(I) that contain tridentate P,N ligands (Figure 1).
For example, catalyst A is highly enantioselective (70–95 ee%)
only with tert-butyl aryl ketones, catalyst B (30–84 ee%) only
with dialkyl and cyclic ketones, whereas catalysts D and F gave
enantioselectivity below 53 and 55% ee, respectively.
Cl
2 (2 mol%)
NaOtBu
OH
R
O
OH
(10 mol%)
N
10
F
2-propanol
50 °C
85%, 97% ee
9
F
Scheme 5. Asymmetric transfer hydrogenation of haloperidol. Reaction condi-
tions: substrate (5 mmol) in 2-propanol (25 mL, 0.2 M), 2 (2 mol%), NaOtBu
(10 mol%), 50 °C, 4 h. Toluene (2.5 mL) was added to solubilize the substrate.
The enantioselectivity (ee%) was determined by chiral HPLC.
In conclusion, we have presented a chiral macrocyclic Mn(I)
catalyst for the asymmetric transfer hydrogenation of a broad
scope of (hetero)aryl alkyl ketones with the best results in terms
3
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COMMUNICATION
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functionalized ketones of biological and medicinal interest. The
high enantioselection derives from attractive CH/π interactions
between the catalyst and the substrate. A mechanistic study is
currently ongoing and its results will be reported in due course.
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5
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Entry for the Table of Contents
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A. Passera, A. Mezzetti*
Page No. – Page No.
Manganese(I)-Catalyzed Asymmetric
Transfer Hydrogenation of Ketones:
Disclosing the Macrocylic Privilege
Wondrous Shape. A manganese(I) complex contaning a chiral (NH)2P2 macro-
cycle catalyzes the asymmetric transfer hydrogenation of a broad scope of 43
ketones with the highest enantioselectivity obtained with this metal so far. Several
non-covalent interactions between the incoming substrate and the macrocylic ligand
account for the excellent enantioselection
6
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