A New Class of Low-Loading Catalysts for Highly Enantioselective, Metal-Free Imine Reduction of Wide General Applicability

Article abstract of DOI:10.1002/cctc.201700052

A new class of chiral Lewis bases for the enantioselective HSiCl₃-mediated reduction of imines was developed. Through extensive catalyst structure optimization, an extremely active species was identified that was able to promote the reduction o

Full text of DOI:10.1002/cctc.201700052

Accepted Article
Title: A new class of low-loading catalysts for a highly enantioselective,
metal-free imine reduction of wide general applicability
Authors: Davide Brenna, Riccardo Porta, Elisabetta Massolo, Laura
Raimondi, and Maurizio Benaglia
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10.1002/cctc.201700052
ChemCatChem
COMMUNICATION
A new class of low-loading catalysts for a highly enantioselective,
metal-free imine reduction of wide general applicability
Davide Brenna, Riccardo Porta, Elisabetta Massolo, Laura Raimondi, and Maurizio Benaglia*
Abstract: A new class of chiral Lewis bases for the enantioselective
HSiCl3-mediated reduction of imines has been developed. Through
an extensive catalyst structure optimization, an extremely active
species was identified, able to promote the reduction of a large
variety of functionalized substrates in high yields and
enantioselectivities typically above 90% with catalyst loading as low
as 0.1-1% mol. The simple experimental procedure, the low cost of
the reagents, the mild reaction conditions, and straightforward
isolation of the product, make the methodology attractive also for
large scale applications. Its synthetic potentiality was demonstrated
by the preparation of advanced intermediates of important APIs,
used in the treatment of Alzheimer and Parkinson diseases,
high yields and enantioselectivities typically higher than 90%,
and with catalyst loadings ranging from 0.1 to 1% mol, a level
that is exceptionally low for organocatalysis. Remarkably, the
new catalysts showed a wide scope and were applied to the
synthesis of differently substituted chiral N-aryl and N-alkyl
amines, including α− and β−amino esters and α−nitro amines,
easily converted in differently functionalized 1,2-diamino
compounds.
hyperparathyroidism,
neuropathic
pains
and
neurological
disorders.The reaction has also been successfully performed in flow
reactors, thus demonstrating the possibility to realize in continuo
processes yielding multigram quantities of product.
The stereoselective reduction of C=N bonds is probably the
most popular approach to synthesize chiral amines.[1] Although
in the last few years remarkable progress has been made in the
development of efficient chiral organometallic complexes for
imines hydrogenation,[2] the high cost of the precious metal
species and their lack of general applicability make the
discovery of new, highly performant catalysts greatly desirable.
Moreover, in the case of C=N bonds reduction, very often quite
high catalyst loadings are required.[3] Metal free catalytic
methodologies represent a viable alternative option, and some
efficient catalytic systems have been reported,[4] but also in
these cases high catalyst loadings are necessary.
Figure 1. A new class of chiral Lewis bases for enantioselective catalytic
hydrosilylation of imines.
Enantiopure picolinamides have been extensively studied as
activators of trichlorosilane.[8] In designing a new class of chiral
Lewis basic catalysts, we took advantage of the well-established
conformational features of chiral imidazolidinones, successfully
used in aminocatalysis.[9] While the picolinamide unit is
responsible of HSiCl3 coordination and chemical activation, the
imidazolidinone scaffold offers many opportunities to tune and
modify the steric requirements and the stereoelectronic
properties of the catalytic system (Figure 1). Therefore, a series
of new chemical entities, featuring different substituents on the
imidazolidinone ring and on the aromatic ring of the amino acid
moiety, were synthesized (Figure 2).
Despite all the recent achievements in the field, the
combination of inexpensive, atoxic, easily available catalyst
capable of performing at the very low loadings typical of
organometallic catalysis, is an unmet challenge for present-day
organocatalysis.[5] Trichlorosilane-based reduction methods may
offer an interesting opportunity in this sense.[6] Being a waste
product of silicon industry, HSiCl3 is an extremely cheap
reagent, readily available in large quantities, that is capable of
reducing C=N bonds with amazing chemoselectivity. Its
coordination with chiral Lewis bases allowed to develop highly
enantioselective catalytic reductions of imines.[7] Here we report
the design and the optimization of a new class of enantiopure
chiral picolinamides, easily prepared in a few steps from amino
acids, such as phenyl-alanine and tyrosine (Figure 1). An
extremely active species has been identified, able to promote
the reduction on a large variety of functionalized substrates in
[*]
Davide Brenna, Riccardo Porta, Prof. Dr. Laura Raimondi, Prof. Dr.
Maurizio Benaglia
Dipartimento di Chimica, Università degli Studi di Milano
Via C. Golgi, 19, 20133 – Milano, Italy
E-mail: maurizio.benaglia@unimi.it
Figure 2. A new class of chiral organocatalysts for the enantioselective
trichlorosilane-mediated ketoimines reduction.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/cctc.201700052
ChemCatChem
COMMUNICATION
Starting from (S)-phenyl alanine, enantiopure Lewis bases
1a-1i were synthesized; the imidazolidinone ring was assembled
via reaction of the N-methyl (S)-phenyl alanine carboxyamide
with different carbonyl derivatives, and then conjugated to
picolinic acid. Analogously, (S)-tyrosine was used to prepare
catalysts 2 – 4 (Figure 2).
catalytic reactors,[11] the enantiopure Lewis base 4 was also
synthesized, to verify the compatibility of the linker, featuring a
triazole ring, with the reaction conditions.[12] Indeed, all catalysts
3a-c and 4 promoted the reduction, in nearly quantitative yields
and with up to 98% enantioselectivity in the case of the O-benzyl
substituted catalyst 3c (entries 12-15).
A preliminary screening of all new picolinamides 1-4 as
catalysts in the trichlorosilane-mediated model reduction of N-
phenyl acetophenone imine 5a at 0 °C allowed to identify the
most promising catalyst candidates (Table 1).
When the behavior of the most promising catalysts 1a, 3a-c and
4 was studied in the reduction of the electron-rich, and therefore
likely poorly reactive, imines 5b-d, some further differences were
evidenced, especially about chemical activity. While catalyst 1a
was unable to promote the reduction of imines 5c-d, chiral
Table 1. Catalyst screening.
picolinamide
4
and particularly the O-benzyl protected
imidazolidinone derivative 3c afforded the expected chiral
amines 6b-d in 99% yield and enantioselectivities ranging from
91 to 97 % (Scheme 1).
PMP
N
PMP
PMP
PMP
HSiCl
HN
3,
HN
HN
cat. (10 mol%)
Entry[a]
1
Catalyst
1a
1a
1b
1c
1d
1e
1f
Yield (%)[b]
e.e. (%)[c]
85
CH Cl 0 °C
2 2,
R
MeO
76
73
57
13
73
90
80
75
76
60
78
98
81
98
99
5b
5c
R= H
R=Me
6b
6c
6d
R= OMe 5d
2[d]
3
92
O
cat.
1a
N
<10%Y; n.d.
no reaction
Bn
N
77%Y; 89% e.e.
10
Py
O
<5
4
O
3a: R = H
3b: R = iPr
3c: R = Bn
93%Y; 96% e.e.
81%Y; 95% e.e.
99%Y; 97% e.e.
95%Y; 93% e.e.
55%Y; 60% e.e.
99%Y; 93% e.e.
99%Y; 85% e.e.
no reaction
Bu
N
N
O
64
5
RO
Py
99%Y; 91% e.e.
<5
O
N
6
Bu
N
4
99%Y; 91% e.e.
89%Y; 90% e.e.
N
99%Y; 93% e.e.
Bn
72
N
N
7
Py
O
O
1g
1h
1i
<5
8
Scheme 1. Comparison of different catalytic activities 1a, 3a-3c and 4.
Reaction conditions: 5 (0.1 mmol), cat. 0.01 mmol, HSiCl3 (0.35 mmol, 35 µL)
in CH2Cl2 (1 mL) at 0°C C;
89
9
48
10
11
12
13
14
15
Table 2. Studies on catalysts loadings with Lewis bases 3c and 4.
2
23
3a
3b
3c
4
94
97
98
92
[a] Reaction conditions: 5a (0.1 mmol), cat. 0.01 mmol, HSiCl3 (0.35 mmol, 35
µL) in CH2Cl2 (1 mL) at 0°C for 18 h; [b] isolated yield; [c] de termined by HPLC
on chiral stationary phase; absolute configuration established by comparison
of optical rotation values; [d] reaction performed at -10 °C.
Entry[a]
Catalyst
Cat. loading
5 mol%
Yield (%)[b]
e.e. (%)[c]
4
4
95
95
86
92
99
93
80
92
81
92
92
97
90
97
1
2[d]
3[e]
4
Since catalyst 1a showed interesting results (entries 1-2), it
was envisioned that a modification on the imidazolidinone ring
could lead to an improved catalyst efficiency. For example, it
was thought the combination of different R1 and R2 residues
(see Figure 1) could force the phenyl ring of the benzylic unit in
a more favourable position, to preferentially shield one face of
the imine and improve enantioselectivity.[10] However, the
structural variations in catalysts 1b-1i did not lead to any positive
results. On the contrary, the introduction of a substituent in para
position of the phenyl ring allowed to identify a few very efficient
catalysts, like compounds 3a-c. In view of the immobilization of
these chiral Lewis base on solid support, to facilitate the
development of continuous flow stereoselective reductions in
5 mol%
4
5 mol%
4
1 mol%
3c
3c
3c
1 mol%
5
0,1 mol%
0,1 mol%
6
7[f]
[a] Eq. A. Reaction conditions: 5b (0.1 mmol), cat. 0.01 mmol, HSiCl3 (0.35
mmol, 35 µL) in CH2Cl2 (1 mL) at 0°C for 18 h; [b] isolated yield; [c] de termined
by HPLC on chiral stationary phase; [d] reaction performed at 25 °C; [e]
reaction time = 2 hours; [f] reaction performed at -20 °C.
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10.1002/cctc.201700052
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COMMUNICATION
Given their exceptional activity, catalysts 3c and 4 were
selected for further studies.[13] In the attempt to lower the catalyst
loading, the reduction of imine 5b was performed with reduced
amounts of chiral Lewis base (Eq. A, Table 2). Noteworthy,
catalyst 4 still worked efficiently at 1 mol% loading, affording the
product in 93% yield and 92% e.e. (entries 1-4); catalyst 3c
showed an even more remarkable activity and promoted the
reduction with 0.1% mol loading in 92% yield at 0°C , and in 80%
yield and 97% e.e. at -20°C. It is worth mentioning that, by
performing the reaction with 0.1 mol% of chiral base, the ACE
(Asymmetric Catalyst Efficiency)[14] of catalyst 3c, based on
entries 6-7 of Table 2, is 375-400, a value that very favourably
compares with either organometallic or organic chiral catalysts,
which in most cases do not go beyond 50-60 ACE values.[7b] To
further demonstrate the efficiency of catalyst 3c, the synthesis of
the chiral amine 6e was successfully accomplished on multi-
gram scale: using 10 mg of catalyst almost 10 grams of
enantiopure amine was obtained, after a single crystallization,
without the need of any chromatographic purification (Eq. B).[15]
Reaction conditions: 5a (0.1 mmol), cat. 0.01 mmol, HSiCl3 (0.35 mmol, 35
µL) in CH2Cl2 (1 mL) at 0°C for 18 h; [a] isolated yield; [b] de termined by HPLC
on chiral stationary phase; [c] reaction performed at -10 °C.
Both catalysts 4 and 3c promoted the reduction of N-aryl and
N- alkyl substituted imines in >90% yield and enantioselectivities
constantly ranging from 90% to 98%. The synthesis of α− and β-
amino esters was also accomplished, in up to 96% e.e. The
reduction of 3-alkoxy-substituted acetophenone imines (5j-l),
either N-benzyl protected (as precursor of primary amine
derivatives), or N-(3-phenylpropyl) substituted (imine 5m),
represents a practical and efficient entry to the synthesis of
enantiomerically pure valuable pharmaceutical compounds,
used in the treatment of Alzheimer and Parkinson diseases,
hyperparathyroidism, neuropathic pains and neurological
disorders (Figure 3). [16]
To test the general applicability of catalysts 3c and 4 the
reduction of a wide variety of imines was investigated (Table 3).
Table 3. Reaction scope.
Figure 3. Chiral amines as valuable pharmaceutically active compounds.
PG
PG
R'
HSiCl3, cat. (10 mol%)
N
HN
CH2Cl2, 18 h, 0 °C
R
R'
R
In view of a possible extension of this catalytic methodology
to the industrial scale, the possibility to perform the reaction in
flow reactors was also preliminarily investigated (Scheme 2).[17]
The reduction of model imine 5a was successfully accomplished
under continuous flow conditions. By running the reaction in a
0.5 ml mesoreactor for 20 minutes at 0°C, the chira l amine 6a
was obtained in 96% yield and 97% e.e. (see the SI).
5e-q
6e-q
Y
e.e
Entry
Imine
Cat.
R
R’
PG
(%)[a] (%) [b]
5e
5e
5f
3c
4
CH3
CH3
Ph
Ph
99
99
93
92
99
94
98
95
98
97
80
80
99
99
80
99
95
85
65
99
98
90
95
96
97
93
96
94
90
90
96
93
98
90
96
85
85
96
95
93
1
2[c]
3
β-napht
β-napht
4-F-
C6H4
4
CH3
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Bn
4-CF3-
C6H4
5g
5h
5h
5i
4
CH3
4
4-NO2-
C6H4
3c
4
CH3
5
4-NO2-
C6H4
CH3
6
4-Cl-
C6H4
Scheme 2. Continuous flow, organocatalytic enantioselective reduction
.
3c
4
CH3
7
4-Cl-
C6H4
5i
CH3
8
In the same fluidic device the chiral α−nitro amine 6q was
also obtained with 88% e.e.; starting from this product the Raney
Ni-catalysed reduction[18] afforded the chiral 1,2-diamine 7, thus
offering the possibility to realize a two steps, in flow, metal-free
process.
3-OMe-
C6H4
9[c]
10
5j
3c
4
CH3
3-OMe-
C6H4
5j
CH3
3-OBn-
C6H4
11[c]
12
5k
5l
4
CH3
3-OBn-
C6H4
4
CH3
The model tentatively proposed to rationalize the steric
course of the enantioselective reduction catalyzed by 3c is
reported in Scheme 3.
13[c]
14[c]
15[c]
16[c]
17[c]
18[c]
19
5m
5m
5n
5o
5o
5p
5p
5q
3c
4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3
(CH2)3Ph
(CH2)3Ph
n-Bu
CH3
3c
3c
4
CH3
CO2CH3
CO2CH3
CH2CO2CH3
CH2CO2CH3
CH2NO2
PMP
PMP
PMP
PMP
PMP
3c
4
20[c]
3c
Scheme 3. Proposed TS for the reduction promoted by catalyst 3c.
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10.1002/cctc.201700052
ChemCatChem
COMMUNICATION
Borrego, E. Álvarez, N. Khiar, I. Fernandez, Org. Lett., 2016, 18,
3258−3261. For pioneer works with aminoacid-derived catalysts see: h)
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Deng, W. Li, X. Zhang, Tetrahedron Lett. 2007, 48, 7934-7937; c) S.
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Zhang, Angew. Chem. Int. Ed. 2011, 50, 7304-7307; f) Y. Jiang, X.
Chen, X. Hu, C. Shu, Y. Zhang, Y. Zheng, C. Lian, W. Yuan, X. Zhang,
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[9] For a review, see: a) G. Lelais, D. W. C. MacMillan, Aldrichimica, 2006,
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Ashton, D. W. C. MacMillan, Science, 2007, 316, 582; c) D. Nicewicz, D.
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[10] See S. G. Ouellet, J. B. Tuttle, D.W. C. Mac-Millan, J. Am. Chem. Soc,
2005, 127, 32 and references cited.
[11] Studies with immobilized catalysts are underway in our group; the results
will be reported in due course.
In model A, that leads to the formation of the experimentally
preferred (R) enantiomer, both the aromatic ring at the imine
carbon and the protecting group at the imine nitrogen do not
experiment the severe steric repulsions that greatly destabilize
TS of model B.
In conclusion, a new class of chiral Lewis bases for imines
hydrosilylation was developed; the most active catalyst
promoted the reduction of a wide variety of functionalized
substrates,
very
often
in
quantitative
yields
and
enantioselectivities that typically were higher than 90%, and in
some instances reached 98%. Remarkably, the chiral Lewis
base of choice efficiently catalyzed the reaction with a catalyst
loading as low as 0.1% mol without any erosion of its
stereoselectivity. The synthesis of enantiopure chiral amines on
multi-gram scale, as well as the possibility to perform the
organocatalytic enantioselective reduction under continuous flow
conditions have been demonstrated.[19] We believe that the
simple experimental procedure, the low cost of the reagents, the
mild reaction conditions and straightforward isolation of the
product after an aqueous work up, the exceptionally low loading
of the metal-free catalytic species, and the possibility to realize
in continuo processes, make the methodology attractive also for
industrial applications.
[12] For the use of triazole ring as linker in the immobilization of chiral
organocatalysts in our previous works see: a) R. Porta, M. Benaglia, F.
Coccia, F. Cozzi, A. Puglisi, Adv. Synth. Catal., 2015, 357, 377-383; b)
R. Porta, M. Benaglia, A. Puglisi, A. Mandoli, A. Gualandi, P.G. Cozzi,
ChemSusChem, 2014, 7, 3534-3540; c) V. Chiroli, M. Benaglia, A.
Puglisi, R. Porta, R. P. Jumde, A. Mandoli, Green Chem., 2014, 16,
2798-2806.
[13] As reported in Scheme 1, also chiral picolinamides 3a and 3b promoted
the reduction with excellent results; however, they proofed to be
catalysts of less general applicability, compared to 3c, that was selected
as catalyst of choice.
Acknowledgements
[14] The definition of ACE was recently proposed in the attempt to compare
and evaluate the efficiency of different catalysts, considering the level of
enantioselectivity and the yield guaranteed by the catalyst, the molecular
weight of the product and of the catalysts itself. See: S. El-Fayyoumy, M.
H. Todd, C. J. Richards, Beilstein J. Org. Chem. 2009, 5, 67.
[15] For experimental details please see the Supporting Information.
[16] For two very recent contributions on the organocatalyzed reduction as
strategy for the synthesis of biologically active chiral amines see: a) V.
N. Wakchaure, P. S. J. Kaib, M. Leutzsch, B. List, Angew. Chem. Int. Ed.
M.B. thanks Università degli Studi di Milano for financial support
(H2020 Transition Grant); D.B., E.M. and R.P. thank Università
degli Studi di Milano for a Ph.D. fellowship.
Keywords: Enantioselective reduction • Trichlorosilane • Chiral
amines • Lewis bases • Organocatalysis
2015, 54, 11852–11856; b) D. Brenna, M. Benaglia,
R Porta, S.
Fernandes, A. J. Burke, Eur. J. Org. Chem. 2016, doi:
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F. Coccia, S. Rossi, A. Puglisi, Symmetry 2015, 7, 1395. For recent
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This article is protected by copyright. All rights reserved.

10.1002/cctc.201700052
ChemCatChem
COMMUNICATION
O
N
NBu
An extremely active Lewis base, able
to promote with catalyst loading low as
0.1-1% mol the HSiCl3-mediated
reduction of a great variety of imines in
high yields and enantioselectivities
typically higher than 90%, was
Davide Brenna, Riccardo Porta,
Elisabetta Massolo, Laura Raimondi and
Maurizio Benaglia*
cat.
Py
O
RO
X
X
HN
Ar
X
R
cat. (0.1 - 5 mol %)
HN
Ar
N
NH
2
Page No. – Page No.
HSiCl
3
Ar
R
A new class of low-loading catalysts
for a highly enantioselective, metal-
free imine reduction of wide general
applicability
NH
2
COOR
Ar
discovered. The reaction has been
efficiently performed also in flow
mesoreactors, thus realizing metal-free
enantioselective catalysis in continuo.
Applications to the synthesis of
Me
Me
Me
Me
Me
N
NH
2
MeO
N
O
N
R
O
H
Me
O
Cl
(R) NPS R-568
N
R=Et: (S)-Rivastigmine
R=H: (S)-Miotine
KCNQ2 opener
advanced intermediates of APIs have
been successfully accomplished.
This article is protected by copyright. All rights reserved.