Catalytic Asymmetric Reductive Condensation of N–H Imines: Synthesis of C2-Symmetric Secondary Amines

Article abstract of DOI:10.1002/anie.201608329

A highly diastereoselective and enantioselective Br?nsted acid catalyzed reductive condensation of N?H imines was developed. This reaction is catalyzed by a chiral disulfonimide (DSI), uses Hantzsch esters as a hydrogen source, and delivers useful C₂-symmetric secondary amines.

Full text of DOI:10.1002/anie.201608329

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201608329
German Edition: DOI: 10.1002/ange.201608329
Organocatalysis
Catalytic Asymmetric Reductive Condensation of N–H Imines:
Synthesis of C2-Symmetric Secondary Amines
Vijay N. Wakchaure and Benjamin List*
Abstract: A highly diastereoselective and enantioselective
À
Brønsted acid catalyzed reductive condensation of N H
imines was developed. This reaction is catalyzed by a chiral
disulfonimide (DSI), uses Hantzsch esters as a hydrogen
source, and delivers useful C2-symmetric secondary amines.
E
nantiomerically pure C2-symmetric secondary amines
represent a privileged structural motif that is featured in
organocatalysts,[1] chiral ligands,[2] and as a substructure of the
phosphoramidite ligand class.[3] In addition, the correspond-
ing chiral lithium amides[4] have been used in enantioselective
deprotonations and as chiral ammonia equivalents in con-
jugate addition reactions.
using Hantzsch ester 3 in the presence of DSI-2a, we found
that instead of primary amine 4, the corresponding C2-
symmetric secondary amine 5a was obtained with promising
diastereo- and enantioselectivity [Eq. (1)].[11]
This product has previously been reported as a byproduct
in a chemoenzymatic dynamic kinetic resolution of racemic
primary amine 4.[12] However, to the best of our knowledge,
À
such an asymmetric reductive condensation of N H imines is
so far unknown. Encouraged by our initial observation, and
considering the various applications of C2-symmetric secon-
dary amines, a systematic exploration of different conditions
was conducted to optimize the reaction (Table 1). The chiral
DSI catalysts 2a–f,[6a,13] which were recently developed in our
laboratory, catalyzed the transformation more rapidly than
alternative phosphoric acid type catalysts (see the Supporting
Such C2-symmetric secondary amines can be efficiently
obtained through asymmetric imine reductions and reductive
aminations of carbonyl compounds.[5] However, these meth-
ods require the stoichiometric use of a chiral amine auxiliary
and are typically limited to commercially available chiral
amines. We now report an alternative approach that involves
a highly diastereoselective and enantioselective reductive
condensation of N-H imines that is catalyzed by chiral
disulfonimide (DSI) and uses Hantzsch esters as a hydrogen
source.
Table 1: Reaction development[a]
Recently, we developed a chiral-DSI-catalyzed highly
enantioselective reduction of N-alkyl imines.[6–9] The reaction
uses a Hantzsch ester as a hydrogen source in the presence of
Boc2O, and provides facile access to several enantioenriched
N-Boc-protected N-alkyl amines. We became interested in
advancing this concept to include the equally attractive but
Entry
Cat.
Solvent
Conv.[%][b]
d.r.[b]
24:1
e.r.[c]
88:12
72:28
84:16
86:14
89.5:10.5
94:6
À
even more challenging unsubstituted N H imines 1. Initially,
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2 f
2 f
2 f
2 f
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
MTBE
92
91
93
91
96
97
93
74
92
15.6:1
24:1
24:1
65:1
99:1
99:1
99:1
99:1
we hoped that this design would lead to direct entry to
enantioenriched primary amines 4 [Eq. (1)]. Such reductions
have rarely been studied and remain a major challenge.[10]
Surprisingly, when investigating the reduction of imine 1a
>99:1
>99:1
>99:1
8[d]
9[e]
MTBE
MTBE
[*] Dr. V. N. Wakchaure, Prof. Dr. B. List
Max-Planck-Institut fꢁr Kohlenforschung
Kaiser -Wilhelm-Platz 1, 45470 Mꢁlheim an der Ruhr (Germany)
E-mail: list@kofo.mpg.de
[a] Reactions were run on a 0.05 mmol scale. [b] Determined by GC
analysis.[11] [c] Determined by HPLC analysis. [d] Without 5 ꢀ MS,
reaction time 48 h. [e] Using 150 mg of Amberlite CG-50 resin instead of
5 ꢀ MS. MTBE=methyl tert-butyl ether.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201608329.
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Information) and also afforded amine 5a with higher
diastereo- and enantioselectivity (entries 1–6). Gratifyingly,
catalyst 2 f, which contains the unusual 2,5-ditrifluoromethyl-
benzene substitution in the 3,3’-position of the backbone,[14]
afforded an excellent d.r. of 99:1 and an e.r. of 94:6 (entry 6).
Furthermore, solvent screening revealed MTBE to be opti-
mal, affording the amine product with an almost perfect e.r. of
> 99:1 (entry 7). In the absence of molecular sieves (MS), the
reaction becomes slower and partial hydrolysis of the imine is
observed, while the diastereo- and enantioselectivity remain
identical (entry 8). Compared to 5 ꢀ MS, Amberlite CG-50
resin under the standard reaction condition gave similar
results (entry 9), thus suggesting that 5 ꢀ MS may trap the
ammonia byproduct, thereby enhancing catalyst turnover.
With the optimal conditions in hand, we next began
investigating the substrate scope of the enantioselective
butyl-substituted imine 1c provided secondary amine 5c in
79% yield and with a d.r. of 99:1 and an e.r. of 99.6:0.4.
Substrates with electron-withdrawing para substituents, such
as fluorine, chlorine, or trifluoromethyl groups, could also be
used, furnishing products 5e–5g with uniformly superb
diastereoselectivity and enantioselectivity. Substitutions at
the meta position are equally well tolerated and both
electron-donating and electron-withdrawing groups provided
the corresponding secondary amines in good yields and with
remarkably high diastereoselectivity and enantioselectivity
(products 5h–5j). Substrates with m-methyl and m-trifluor-
omethyl groups (1h, 1j) were less reactive and required
longer reaction time. o-Fluoro-substituted imine 1k also
reacted more slowly and provided secondary amine 5k in
49% yield and with a d.r. of 19:1 and an e.r. of 98:2. m,p-
Disubstitution led to similar results (product 5l). Interest-
À
À
reductive condensation of N H imines (Table 2).
ingly, the 2-naphthyl N H imine afforded amine product 5m
À
A variety of N H imines efficiently underwent the
in good yield and with a d.r. of 99:1 and an e.r. of 99.7:0.3. A
heterocyclic substrate, pyridine derivative 1n, efficiently
underwent the reductive condensation to afford the corre-
sponding secondary amine 5n in 90% yield and with a d.r. of
99:1 and an e.r. of 98.5:1.5. This result further underscores the
remarkable base tolerance of our reaction. Unfortunately, the
reductive condensation in the presence of disulfonimide 2 f
(5.0 mol%) to afford the corresponding C2-symmetric secon-
dary amines in good yields and with outstanding diastereo-
and enantioselectivity. Electron-donating para substituents
are well tolerated (products 5b–5d). For example, p-tert-
À
corresponding phenyl,ethyl-substituted N H imine and an
À
aliphatic cyclohexyl,methyl-substituted N H imine did not
react to the desired product.
Table 2: Substrate scope.[a]
Preliminary studies towards applying the newly available
C2-symmetric secondary amines in asymmetric synthesis, in
which they were used as a lithium amide base in a benchmark
enol silane synthesis, and as part of a new phosphoramidite
ligand for use in the asymmetric addition of arylboron
reagents to acyclic enones,[15] confirmed their promise. Both
reactions investigated gave results comparable to analogous
known transformations.[16]
We currently envision a catalytic cycle that is initiated by
the protonation of imine 1a by chiral DSI-2 f (Scheme 1). The
resulting iminium ion pair A undergoes reaction with
Hantzsch dihydropyridine 3 to give enantiomerically enriched
primary amine salt B and the corresponding Hantzsch
pyridine. Subsequently, amine B undergoes a transimination
with substrate 1a, first to produce aminal C, which then
[a] Reactions run on 0.25 mmol scale. The e.r. was determined by HPLC.
The d.r. was determined by GC, NMR, or LC analysis. The absolute
configurations of 5a, ent-5a, and 5d were determined by comparing
known optical rotation values (see the Supporting Information).
[b] Using (S)-DSI-2 f. [c] 48 h. [d] 72 h.
Scheme 1. Proposed catalytic cycle.
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c) N. Levi, R. Neumann, ACS Catal. 2013, 3, 1915 – 1918; d) S.
liberates ammonia to form the secondary iminium ion pair
D.[17] Finally, a second reduction of intermediate D provides
diastereo- and enantioenriched secondary amine product 5a.
It should be noted that we observed some degree of kinetic
resolution in the reduction of iminium ion pair D, which
further enhances the enantiomeric ratio of our C2-symmetric
secondary amine products (see the Supporting Information).
This perhaps explains the superb enantioselectivity observed.
In summary, we have developed an asymmetric Brønsted
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À
acid catalyzed reductive condensation of N H imines. The
reaction is catalyzed by a disulfonimide catalyst, uses
a Hantzsch ester as hydrogen source, and provides facile
access to several C2-symmetric secondary amines in good
yields and with remarkably high diastereo- and enantioselec-
tivity. Remarkably, with amine 5, ammonia, and the Hantzsch
pyridine, our reaction delivers three fairly basic products and
yet turnover with our DSI Brønsted acid catalyst is main-
tained. Selected secondary amine products have already
shown promise as chiral lithium amide bases in an enantio-
selective enol silane synthesis and as a subunit of a phosphor-
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reagents to acyclic enones.
Acknowledgements
Generous support by the Max-Planck-Society and the Euro-
pean Research Council (Advanced Grant “High Performance
Lewis Acid Organocatalysis, HIPOCAT”) is gratefully
acknowledged. We thank the members of our NMR, GC,
MS and HPLC departments, and Markus Leutzsch for their
excellent support.
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Keywords: Brønsted acids · C2-symmetric secondary amines ·
disulfonimide · organocatalysis · reduction
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[17] One referee suggested the possible involvement of a 1,3-hydride
shift in intermediate D, which we can neither exclude nor
confirm at this point.
Received: August 25, 2016
Published online: && &&, &&&&
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Communications
Organocatalysis
Acids for base building: A highly diaste-
reoselective and enantioselective
V. N. Wakchaure, B. List*
&&&& — &&&&
Brønsted acid catalyzed reductive con-
À
densation of N H imines was developed.
Catalytic Asymmetric Reductive
Condensation of N–H Imines: Synthesis
of C2-Symmetric Secondary Amines
This dimerizing reduction is catalyzed by
a chiral disulfonimide (DSI), uses
Hantzsch esters as a hydrogen source,
and delivers useful C2-symmetric secon-
dary amines.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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