Manganese-Catalyzed Asymmetric Hydrogenation of Quinolines Enabled by π–π Interaction**

Article abstract of DOI:10.1002/anie.202013540

The non-noble metal-catalyzed asymmetric hydrogenation of N-heteroaromatics, quinolines, is reported. A new chiral pincer manganese catalyst showed outstanding catalytic activity in the asymmetric hydrogenation of quinolines, affording high yields and enantioselectivities (up to 97 % ee). A turnover number of 3840 was reached at a low catalyst loading (S/C=4000), which is competitive with the activity of most effective noble metal catalysts for this reaction. The precise regulation of the enantioselectivity were ensured by a π–π interaction.

Full text of DOI:10.1002/anie.202013540

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Accepted Article
Title: Manganese-Catalyzed Asymmetric Hydrogenation of Quinolines
Enabled by π–π Interaction
Authors: Chenguang Liu, Mingyang Wang, Shihan Liu, Yujie Wang,
Yong Peng, Yu Lan, and Qiang Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202013540
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Manganese-Catalyzed Asymmetric Hydrogenation of Quinolines
Enabled by – Interaction
Chenguang Liu,[a] Mingyang Wang,[a] Shihan Liu,[c] Yujie Wang,[a] Yong Peng,[a] Yu Lan *[b], [c] and
Qiang Liu*[a]
[a]
[b]
[c]
C. Liu, M. Wang, Y. Wang, Y. Peng and Prof. Dr. Q. Liu*
Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University
Beijing 100084, China
E-mail: qiang_liu@mail.tsinghua.edu.cn.
Prof. Dr. Y. Lan*
Institute of Green Catalysis, College of Chemistry, Zhengzhou University
Zhengzhou, Henan 450001, China
E-mail: lanyu@cqu.edu.cn.
S. Liu and Prof. Dr. Y. Lan*
Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University
Chongqing 400030, China
Abstract: The first example of non-noble metal-catalyzed asymmetric
hydrogenation of N-heteroaromatics is reported. A new chiral pincer
manganese catalyst showed outstanding catalytic activity in the
asymmetric hydrogenation of quinolines, affording high yields and
enantioselectivities (up to 97% ee). A turnover number of 3840 was
reached at a low catalyst loading (S/C=4000), which was competitive
earth and exhibits low toxicity, is another ideal choice.[13] Mn-
catalyzed hydrogenation reactions have seen significant
progress[14] since the seminal work of Beller’s group in 2016.[15] In
particular, Mn-catalyzed AH of ketone has also been reported[16]
,
among which Ding, Han and co-workers developed a highly
efficient chiral manganese catalyst.[16c, 16d] This demonstrates the
with the activity of most effective noble metal catalysts for this reaction. great potential of Mn-based catalysts in AH. However, no
The precise regulation of the enantioselectivity were ensured by a –
 interaction.
example of Mn-catalyzed AH of unsaturated compounds other
than ketones has been reported to date.
Optically active 1,2,3,4-tetrahydroquinolines (THQs), as an
important structural motif, widely found in bioactive molecules and
natural products.[1] Numerous methods for constructing these
chiral skeletons have been explored.[2] Significantly, the direct
asymmetric hydrogenation (AH) of quinolines remains one of the
most efficient approaches to producing these compounds.[3] With
the development of catalytic systems based on precious metals,
including Ir[4], Ru[5], Rh[6], and Pd[7], both the efficiency and
substrate scope of the AH of quinolines have been greatly
improved (Scheme 1A). Specifically, iridium catalysts containing
chiral bisphosphine ligands have proven to be effective for AH of
quinolines activated by iodine since the pioneering work of Zhou
in 2003.[4a] Furthermore, Fan, Chan, and coworkers have shown
cationic complex Ru(OTf)(TsDPEN)-(η6-cymene) to be a state-of-
the-art catalyst for this transformation, affording outstanding
enantioselectivity and a broad substrate scope.[5a, 5c] In addition to
transition metal catalysts, frustrated Lewis pairs (FLPs) are also
powerful catalysts for the AH of quinolines.[8] Although the above
catalytic systems remain unsurpassed at present, they still have
some shortcomings. For precious metal catalysts, issues of high
cost, uncertain supply, and toxicity concerns remain unsolved.
Meanwhile for FLP catalysis, preparation of chiral bisborane
catalysts are usually complicated and a higher catalyst loading is
required compared with transition metal catalysis. Such
limitations may restrict their wide applications on a large scale.
Therefore, the development of more sustainable and practical
catalysts for the AH of quinolines remains a highly desirable, but
challenging task.
Scheme 1. AH of 2-substituted quinolines.
Following our continued pursuit of Mn-catalyzed
(de)hydrogenation reactions[17], herein we disclosed an Mn-
catalyzed AH of quinolines with up to 97% ee and a maximum
turnover number (TON) of 3840. The high reactivity and effective
enantioselectivity control of this chiral catalyst are enabled by a
newly designed chiral NNP tridentate ligand (Scheme 1B). To our
knowledge, this is the first example of AH of N-heteroaromatics
catalyzed by a first-row earth-abundant transition metal.
In a recent study, we found that an imidazole based NNP-Mn
pincer catalyst performed with high efficiency in the
hydrogenation of N-heteroaromatics owing to the enhanced
electron-donating ability and low steric hindrance of the imidazole
group.[17c, 18] Inspired by this ligand effect, we aimed to design an
imidazole-based chiral NNP-tridentate ligand for the Mn-
catalyzed AH of quinolines. Coincidentally, Zhong and co-workers
recently developed in-situ formed Mn(I) catalysts containing
imidazole-based chiral NNP tridentate ligands, which enabled the
To achieve such a goal, the application of non-noble metals,
such as iron[9], cobalt[9d, 9f, 10] and nickel[11], to the development of
new AH catalysts is
manganese, which is the third most abundant transition metal on
a . Accordingly,
feasible strategy[12]
1
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10.1002/anie.202013540
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enantioselective
hydrogenation
of
unsymmetrical
reaction efficiency (see Supporting Information for details). The
best result was achieved using Mn(CO)5Br (2.0 mol%), SL1c (2.2
mol%), KOtBu (10 mol%), and 1,4-dioxane as solvent at 80 oC.
To elucidate the structure of in-situ formed active catalyst, we
synthesized the NNP-pincer manganese complex by reacting
Mn(CO)5Br with saturated pincer ligand SL1c’ (Scheme 3a). The
catalytic activity of Mn-2c was further evaluated for comparison
with the performance of in-situ formed catalytic systems. A similar
yield and enantioselectivity were obtained using well-defined
catalyst Mn-2c and the catalytic system formed in-situ from
Mn(CO)5Br and SL1c’ (or SL1c). In addition, it was demonstrated
that a mixture of imine ligand SL1c and Mn(CO)5Br could be
converted to the saturated complex Mn-2c under hydrogen
pressure, which was an active catalyst precursor (see Schemes
S1 and S2 for details).
benzophenones.[19] In this case, the use of ligand SL1a with a
bulky substituent on the N-atom of the benzo[d]imidazole
segment was essential for achieving a high enantioselectivity.
Initially, we attempted to use SL1a for the hydrogenation of 2-
methylquinoline 3a in the presence of Mn(CO)5Br as the catalyst
precursor (Scheme 2). However, low conversion and moderate
enantioselectivity were observed. We hypothesized that this
sterically hindered ligand prevented the coordination of bulky
substrates to the metal center and reduced the reactivity of the
Mn-H species.
Scheme 2. Ligand Screening. Reaction conditions: 3a (0.25 mmol), Mn(CO)5Br
(2.0 mol%), SL1 (2.2 mol%), and KOtBu (20 mol%) in 1,4-dioxane (0.5 mL) at
80 C for 16 h. Yields (%) and enantioselectivities (%ee) were determined by GC
and chiral-phase HPLC.
This unsatisfactory result reminded us of our previous work, in
which mechanistic studies showed that both the steric and
electronic effects of the heterocyclic segment in the ligand are
crucial for the reactivity.[17c] Accordingly, we envisaged controlling
the reactivity and enantioselectivity by regulating the structures of
heterocycle motifs in the ligands. Improved yield and reduced
enantioselectivity (45% conv, 51% ee) were obtained by changing
the substituent on N-atom from a phenyl to methyl group (SL1b).
Notably, 3a was almost quantitatively converted into product 4a
with excellent reversed enantioselectivity (97% ee) by further
changing the methyl group to an H-atom (SL1c). These results
showed that reduced steric hindrance on the N-atom of the
benzo[d]imidazol group was highly important for increasing both
reactivity and enantioselectivity. Furthermore, imidazole-based
NNP tridentate ligands were synthesized to confirm this
conjecture. Compared with the methyl-substituted ligand (SL1e),
the NH-imidazole-based ligand (SL1d) also furnished 4a with a
substantially increased yield and fully reversed configuration
(88% conv, 94% ee). This comparison again highlights the
essential effect of the less hindered NH unit. Monoaryl substituted
imidazole (mixture of 4/5-tautomers[20]) ligand SL1f was also
synthesized to further investigate the substituent effect on the
imidazole ring, while a decreased enantioselectivity was observed.
Other reaction parameters were also optimized to improve the
Scheme 3. Synthesis and reactivity of pincer complexes Mn-2.
The NH moiety on pincer ligands can greatly impact the
reactivity in catalytic hydrogenation via metal–ligand
cooperation.[21] To investigate the effect of two NH moieties on
optimal catalyst Mn-2c, two N-methylated complexes, Mn-2b and
Mn-2g, were prepared and their catalytic activities were evaluated
(Scheme 3b). A much lower yield and ee value were observed for
the AH of 3a using Mn-2b as catalyst compared with the result
using Mn-2c. However, almost no conversion was observed when
using complex Mn-2g as catalyst. These results indicated the
strong beneficial influence of cooperative N–H functionality on this
transformation. Specifically, the central NH group was crucial for
reactivity via metal–ligand cooperation. Although the imidazole-
NH motif also influenced the reactivity, it was more important for
achieving high enantioselectivity owing to its very low steric
hindrance. Density functional theory (DFT) calculations were
conducted to understand origin of chirality in the AH of 3a.
Analysis of the noncovalent interactions (NCI) showed that 12-ts
was calculated to be more stable than 15-ts by a free energy of
2
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2.0 kcal/mol, owing to the – nonbonding interaction between
the imidazole ring and C=N double bond in 12-ts (Figure 1). This
was in agreement with the experimental results. Therefore, the S-
configured product was preferentially formed with excellent
enantioselectivity. The NH unit of the imidazole motif in the ligand
ensured an effective – interaction owing to its small volume,
playing a key role in enantio-induction.
Figure 1. NCI analysis of 12-ts and 15-ts (blue: attraction; green: weak
interaction; red: repulsion). Relative Gibbs free energies (in kcal/mol) are
reported in parentheses.
With optimized reaction conditions in hand, the scope of 2-
substituted quinoline substrates was studied (Scheme 4). A wide
range of substrate(3b-3j) with substituents on benzene ring were
hydrogenated to the corresponding chiral 1,2,3,4-THQs (4b-4j)
with ee values ranging from 91% to 97%. Notably, other reducible
functional groups, such as halogens (4b-4f), and carbon–carbon
double(4i) and triple(4j) bonds, were all well tolerated (See Table
S3 for a test of tolerance for additional functional groups.). Various
2-benzyl substituted quinolines, bearing substituents with
different electronic properties, were converted to the
corresponding products (4k-4n) effectively in 82%–99% yields
with 89%–97% ee values. This method was also proved to be
applicable to the AH of other 2-substituted (n-pentyl, n-octyl,
isopropyl, cyclohexyl, phenemyl and distal olefins) substrates (3o-
3q, 3s-3t, 3v-3w), with excellent yields and ee values (86-93%).
Furthermore, substrates bearing other heteroaromatics (furan (3r),
pyridine (3u), and thiophene (3x)) were also efficiently
hydrogenated, affording 90%–93% ee values with the additional
heterocycles untouched. Notably, chiral THQs 4d, 4s and 4q were
key intermediates for the synthesis of natural products (S)-
Scheme 4. AH of 2-substituted quinoline. Reaction conditions: 3 (0.25 mmol),
Mn(CO)5Br (2.0 mol%), SL1c (2.2 mol%), and KOtBu (10 mol%) in 1,4-dioxane
(0.5 mL) at 80 C for 16 h. [a] The percentages shown are yields of isolated
products and ee values in that order. [b] 20 mol% KOtBu was used. [c] 20 mol%
KOtBu was used at 110 C. [d] SL1d (2.2 mol%) and 20 mol% KOtBu were used
at 110 C. [e] Saturated ligands SL1c’ or SL1d’ (2.2 mol%) was used. [f] SL1f
was used. [g] SL1d was used.
The hydrogenation products of bis(quinoline-2-yl)-methanes
are synthetic precursors for chiral N-heterocyclic carbene (NHC)
ligands[24]. This new catalytic system was applied to constructing
such compounds containing two chiral centers (Scheme 5). The
AH of various bis(quinoline-2-yl)-methanes bearing methyl,
isopropyl and phenyl groups gave the desired products (6a–6d)
with excellent stereoselectivities. Subsequent treatment of (R, R)-
6c with triethyl orthoformate and NH4BF4 afforded six-membered
rigid chiral NHC ligand precursor 7c in 97% yield.
To further evaluate the efficiency of this catalytic system, a
gram-scale reaction was performed with a catalyst loading of
0.025 mol% (Scheme 6a). Excellent enantioselectivity was
maintained with a TON of 3840 achieved. The synthetic utility of
flumequine[22]
respectively.
,
(+)-angustrureine[23] and (-)-cuspareine[23]
,
Various 2-aryl substituted quinolines were subsequently
subjected to Mn-catalyzed AH. A further ligand screening showed
that ligand SL1f gave the best results for these substrates
(Scheme S3), with 63%-97% yields and 83%-97% ee values.
Various substituents on the phenyl ring were well tolerated (4z-
4ac). Notably, a furan-substituted quinoline was also a suitable
substrate for this transformation (4ad).
3
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this Mn-catalyzed AH was demonstrated by the synthesis of a
drug lead compound (Scheme 6b). The enantiomer of compound
10 has been reported as an effective γ-secretase inhibitor for the
treatment of Alzheimer’s disease.[25] Synthesis of this molecule
started with the AH of commercially available substrate 3ae,
followed by sulfonylation to give sulfonamide 8. Deprotection of
methyl group provided chiral alcohol 9, which could be converted
to final product 10 with retention of the enantioselectivity.[26] This
is the first example of the enantioselective synthesis of 10 via
asymmetric catalysis, which is a more sustainable process
compared with the reported chiral resolution protocol.[26]
In summary, we have developed the first non-noble metal-
catalyzed asymmetric hydrogenation of N-heteroaromatics, using
a newly designed chiral manganese catalyst. This catalytic
system was applicable to the asymmetric hydrogenation of 2-
substituted quinolines and bis(quinoline-2-yl)-methanes with
excellent diastereoselectivities and enantioselectivities. Further-
more, a TON of 3840 was achieved, along with excellent yields
and enantioselectivities, demonstrating the high efficiency of this
newly designed chiral manganese catalyst.
Acknowledgements
This project was supported by the National Natural Science
Foundation of China (21822106 and 91845107) and the
Foundation of the Department of Education of Guangdong
Province (2018KZDXM070 and 2019KZDXM052).
Keywords: Manganese • Asymmetric hydrogenation • Chiral
ligand • N-Heteroaromatics • Metal–ligand cooperation
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10.1002/anie.202013540
Angewandte Chemie International Edition
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Table of Contents
First example of non-noble metal-catalyzed asymmetric hydrogenation of N-heteroaromatics has been realized by using a well-defined
chiral pincer manganese catalyst, with up to 97% ee and 3840 TON.
6
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