Chiral Bronsted Acids Catalyze Asymmetric Additions to Substrates that Are Already Protonated: Highly Enantioselective Disulfonimide-Catalyzed Hantzsch Ester Reductions of NH-Imine Hydrochloride Salts

Article abstract of DOI:10.1055/s-0040-1706413

While imines are frequently used substrates in asymmetric Bronsted acid catalysis, their corresponding salts are generally considered unsuitable reaction partners. Such processes are challenging because they require the successful competition of a catalytic amount of a chiral anion with a stoichiometric amount of an achiral one. We now show that enantiopure disulfonimides enable the asymmetric reduction of N-H imine hydrochloride salts using Hantzsch esters as hydrogen source. Our scalable reaction delivers crystalline primary amine salts in great efficiency and enantioselectivity and the discovery suggests potential of this approach in other Bronsted acid catalyzed transformations of achiral iminium salts. Kinetic studies and acidity data suggest a bifunctional catalytic activation mode.

Full text of DOI:10.1055/s-0040-1706413

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–F
letter
A
en
V. N. Wakchaure et al.
Letter
Synlett
Chiral Brønsted Acids Catalyze Asymmetric Additions to Sub-
strates that Are Already Protonated: Highly Enantioselective
Disulfonimide-Catalyzed Hantzsch Ester Reductions of NH–Imine
Hydrochloride Salts
Vijay N. Wakchaure
F3C
CF3
Carla Obradors
Benjamin List*
NH2Cl
DSI (0.5 mol%)
Hantzsch ester
NH3Cl
0
0
0
0-0
0
0
2-9
8
0
4-
5
9
9
X
O
O
CF3
S
S
O
O
F3C
RT, 24 h
Max-Planck-Institut für Kohlenforschung,
Kaiser-Wilhelm-Platz 1, 45470, Mülheim
an der Ruhr, Germany
N
H
tBu
tBu
CF3
95% [4.8 g]
e.r. = 99:1
F3C
no chromatography
DSI
list@kofo.mpg.de
F3C
CF3
Received: 19.06.2020
Accepted after revision: 13.07.2020
Published online: 14.08.2020
R
N
HX* (cat.)
Nu NHR
(1)
well established
unprecedented
R2
R1
H
Nu
*
R2
R1
DOI: 10.1055/s-0040-1706413; Art ID: st-2020-r0356-l
Abstract While imines are frequently used substrates in asymmetric
Brønsted acid catalysis, their corresponding salts are generally consid-
ered unsuitable reaction partners. Such processes are challenging be-
cause they require the successful competition of a catalytic amount of a
chiral anion with a stoichiometric amount of an achiral one. We now
show that enantiopure disulfonimides enable the asymmetric reduction
of N–H imine hydrochloride salts using Hantzsch esters as hydrogen
source. Our scalable reaction delivers crystalline primary amine salts in
great efficiency and enantioselectivity and the discovery suggests po-
tential of this approach in other Brønsted acid catalyzed transforma-
tions of achiral iminium salts. Kinetic studies and acidity data suggest a
bifunctional catalytic activation mode.
H
R
Cl–
N
–
HX* (cat.)
Nu
Nu NH R
Cl
2
(2)
R2
R2
R1
*
R1
H
competition of catalytic enantiopure anion vs. stoichiometric chloride
Scheme 1 The challenge of using iminium salts in asymmetric Brønsted
acid catalysis.
lyze highly enantioselective Hantzsch ester reductions of
N–H imine hydrochloride salts.
Enantiopure, -chiral amines represent an important
pharmacophore that can be found in a vast number of bio-
logically active substances.2 Catalytic asymmetric imine re-
ductions and reductive aminations of carbonyl compounds
are efficient approaches toward these motifs.3 Enantiose-
lective Brønsted acid organocatalysis has contributed with
a diverse palette of methodologies using silanes, boranes,
and Hantzsch esters as the hydrogen source.4–7 Despite
these advances, such reductions have generally been limit-
ed to N-aryl or N-alkyl imines (Scheme 1, eq. 1). The asym-
metric catalytic reduction of unsubstituted N–H imines
would be an attractive strategy to directly furnish valuable
primary amines. However, such reductions have been less
studied and only very few examples appear in
the literature.8,9 A notable exception by Zhang et al. is the
Key words Brønsted acids, N–H imine hydrochloride salt, primary
amine, disulfonimide (DSI), organocatalytic reduction
Chiral Brønsted acids are powerful organocatalysts for a
great variety of asymmetric nucleophilic additions to
imines (Scheme 1, eq. 1).1 In such reactions, the imine is
protonated by the chiral Brønsted acid, with the resulting
chiral anion directing the enantiofacial differentiation upon
attack of the nucleophile onto the iminium cation. In con-
trast, the use of iminium salts in asymmetric Brønsted acid
catalysis has been entirely unprecedented (Scheme 1, eq. 2).
This limitation of asymmetric Brønsted acid catalysis is
perhaps unsurprising because additions to such salts would
require overcoming the background reactivity mediated by
a stoichiometric amount of a strong achiral acid with a cat-
alytic amount of a chiral one. Here we show that unique en-
antiopure disulfonimides (DSI) can be designed that cata-
rhodium/bis(phosphine)thiourea-catalyzed
asymmetric
high-pressure hydrogenation (10 atm) of N–H imine hydro-
chloride salts, leading to excellent yields and enantioselec-
tivities via anion-binding catalysis.8a
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
V. N. Wakchaure et al.
Letter
Synlett
Our previous studies using N–H imines in Brønsted acid
catalysis revealed a competitive transimination reaction of
the intrinsically nucleophilic primary amine product with
the starting imine. Consequently, we observed the enanti-
oselective formation of C2-symmetric secondary amine
products, instead of the desired primary amines.10 We
speculated that if N–H imine hydrochloride salts would be
used instead of the free imines, the corresponding ammoni-
um salt products should not engage in the transimination,
thereby potentially preventing the reductive dimerization.
However, while anion-binding catalysis has shown utility in
addition reactions to iminium salt equivalents,11 the intro-
duction of a stoichiometric, achiral anion (i.e., Cl–) renders
such a reaction design highly challenging, as the underlying
principle of asymmetric-counteranion-directed catalysis
(ACDC)12 is undermined. Nonetheless, we speculated that a
Brønsted acid catalyst stronger than HCl (pKa = 10.3 in
CH3CN) could rapidly exchange the counterion of the N–H
imine salt and overcome the background reactivity. Alter-
natively, a catalyst enabling a bifunctional mechanism, in
which the nucleophile also interacts with the catalyst,
could possibly be used to overcome the background reac-
tivity.13
We commenced our studies with the reduction of N–H
imine HCl salt 1a in the presence of Hantzsch ester 2 as the
hydrogen source using catalyst DSI-3a4c,10,14 (pKa = 8.5 in
CH3CN). Remarkably, the catalyst indeed outperformed the
background reactivity (20%, Table 1, entry 1), and the corre-
sponding primary amine HCl salt 4a was obtained with
promising enantioselectivity (entry 2). A systematic cata-
lyst development (entries 3 and 4) led to a sequential in-
crease of the steric bulk at 3,3′-positions of the (S)-BINOL-
derived backbone. Gratifyingly, catalyst 3c, with the novel
3,5-bis[3,7-bis(trifluoromethyl)naphthalen-1-yl]phenyl
substituent, afforded an excellent e.r. of 97.5:2.5 (entry 4).
A solvent screening revealed a 1:2 mixture of MTBE–MeCy
to be optimal, affording the amine HCl salt product with a
high e.r. of 99:1 (entry 7). Moreover, the catalyst loading
can be reduced to 2 mol% with negligible deterioration of
enantioselectivity (entry 8).
The insolubility of the amine hydrochloride product in
the solvent mixture allowed us to isolate it without column
chromatography, but rather via a simple filtration. After
completion of the reaction, the mixture was filtered
through Celite and washed with a mixture of MTBE/isohex-
ane, which removes the catalyst, excess of Hantzsch ester,
and the Hantzsch ester oxidation product. In contrast, the
desired amine HCl salt remains on the Celite and was col-
lected by washing with a mixture of MeOH–CH2Cl2 in >99%
purity (based on 1H NMR). It is noteworthy that this proce-
dure led to a slight enhancement of enantiopurity (crude
e.r. = 98.5:1.5, after workup e.r. = 99:1).
Table 1 Optimization of the Reaction Conditionsa
tBuO2C
CO2tBu
2 (1.4 equiv)
N
H
NH2Cl
NH3Cl
DSI (5 mol%), 5 Å MS
With the optimized reaction conditions in hand, we
next explored the scope of the enantioselective reduction
of N–H imine HCl salts (Scheme 2).15
solvent (0.033 M), RT, 24 h
1a
4a
CF3
CF3
Ar =
Ar
O
A variety of N–H imine HCl salt substrates were effi-
ciently reduced in the presence of DSI-3c (2 mol%) to afford
the corresponding primary amine HCl salts in good yields
and with excellent enantioselectivities. N–H imine HCl salts
bearing electron-donating para substituents are well toler-
ated. For example, p-tert-butyl-substituted imine HCl salt
1b provided amine HCl salt 4b in 81% yield and with an e.r.
of 99.5:0.5. Similarly, p-trihexylsilyl- and p-methoxy-sub-
stituted iminium salts cleanly provide the products 4c and
4d with excellent enantioselectivity. Substrates with elec-
tron-withdrawing para substituents, such as fluorine or
chlorine atoms, could also be used, furnishing products 4e
and 4f with excellent enantioselectivity. Substitutions at
the meta position are equally well tolerated and both elec-
tron-donating and electron-withdrawing groups provided
the corresponding amine HCl salts in good yields and excel-
lent enantioselectivities (products 4g–j). m-Methoxy sub-
strate (1h) was found to be less reactive and required 5
mol% catalyst loading. o-Fluoro-substituted imine HCl salt
1k also reacted more slowly and provided amine HCl salt
4k in 92% yield and with an e.r. of 99:1. m,p-Disubstitution
led to similar results (product 4l). 2-Naphthyl N–H imine
O
F3C
S
F3C
F3C
CF3
CF3
NH
CF3
S
O
O
3a
Ar
F3C
3b
F3C
3c
DSI
Entry
Catalyst Solvent
Conv. (%)b
e.r.c
–
1
–
MTBE
MTBE
MTBE
MTBE
MeCy
CHCl3
20
2
3a
3b
3c
3c
3c
3c
3c
full
full
full
75
83.5:16.5
91:9
3
4
97.5:2.5
99:1
5
6d
7
full
full
full
93:7
MTBE–MeCy (1:2)f
MTBE–MeCy (1:2)f
99:1
8e
98.5:1.5
a Reactions were performed on a 0.03 mmol scale.
b Determined by GC.
c Determined by HPLC, see the Supporting Information.
d 5 h.
e 2 mol% of catalyst.
f MTBE = methyl tert-butyl ether; MeCy = methylcyclohexane.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
V. N. Wakchaure et al.
Letter
Synlett
Concerning the reaction mechanism, the following ob-
servations have been made: both salts 1a and 4a are essen-
tially insoluble in MTBE or MeCy and our reaction generally
occurs under heterogeneous conditions. However, even un-
der completely homogeneous conditions (in CHCl3), the re-
action proceeds efficiently and with high enantioselectivity
(e.r. = 93:7, Table 1, entry 6).16 Furthermore, we found that
the p-trihexylsilyl-substituted imine salt 1c was completely
soluble in MeCy and efficiently underwent the reduction
with 5 mol% of DSI-3c with moderate enantioselectivity
(e.r. = 74.5:25.5). Remarkably though, slow addition of
imine salt 1c to the reaction mixture resulted in 74% yield
and an e.r. of 97.5:2.5 (Scheme 2). Apparently, slowly add-
ing the substrate suppresses the non-enantioselective back-
ground reaction, suggesting the chiral DSI counterion to be
catalytically more efficient than the chloride counterion.
These results exclude the involvement of ‘anionic phase-
transfer catalysis’, an elegant approach developed by Toste
et al.17
NH2Cl
NH3Cl
DSI-3c (2 mol%)
R2
R2
R1
R1
2 (1.4 equiv), 5 Å MS
MTBE–MeCy (0.033 M), RT, 24 h
1
4
NH3Cl
NH3Cl
NH3Cl
4c
(nhex)3Si
tBu
4a
4b
74%, e.r. = 97.5:2.5a,b
NH3Cl
93%, e.r. = 99:1
81%, e.r. = 99.5:0.5
NH3Cl
NH3Cl
MeO
F
Cl
4d
4e
4f
88%, e.r. = 99.5:0.5c
95%, e.r. = 99.5:0.5
85%, e.r. = 98:2
NH3Cl
NH3Cl
NH3Cl
MeO
Cl
4h
4i
4g
83%, e.r. = 97:3a
93%, e.r. = 99:1
94%, e.r. = 98.5:1.5
NH3Cl
F
NH3Cl
NH3Cl
MeO
F3C
Finally, we studied the effect of the catalyst structure on
the reaction rate toward rationalizing the high enantiose-
lectivity of our methodology and proposing a reasonable
overall mechanism. Monitoring the reduction of iminium
salt 1a by 1H NMR in CDCl3 indeed revealed a great acceler-
ation when comparing DSI-3a (pKa = 8.5) and HCl
(pKa = 10.3; Scheme 4, a). This observation is consistent
with our initial hypothesis that the higher acidity of the DSI
catalyst could aid in surpassing the background reactivity,
providing a more efficient pathway to the enantiopure
product. However, a significant increase of the reaction rate
was also observed when using the less acidic and acyclic
bisaryldisulfonimide 5a as the catalyst (pKa = 10.2). Accord-
ingly, it is not only the acid strength but possibly also the
bifunctional nature of the DSI motif that facilitates the cata-
lytic and enantioselective pathway.13 Indeed, a progressive
increase in the pKa slowly decreased the reaction rate from
catalyst 5d (pKa = 8.2) to 5a (10.2), 5b (11.3), 5c (12.0), and
saccharin 6 (14.6).
In contrast, the more acidic aryl trifluoromethyldisul-
fonimide 7 (pKa = 5.6) moderately decelerates the reaction,
presumably due to an insufficient basicity of its counterion.
Furthermore, cyclic catalyst DSI-3a, bearing aromatic 3,3′-
substituents, outperforms chemically similar though acy-
clic catalysts such as bisaryldisulfonimide 5d reasonably
due to -stacking interactions with the substrate, which
may accelerate ion pairing and the transfer hydrogenation.
Based on these studies, we propose a catalytic cycle that
is initiated by a fast counteranion exchange between imine
salt 1a and DSI-3c.18 The resulting iminium ion pair A rap-
idly reacts with Hantzsch ester 2 in a bifunctional fashion
(Scheme 4, b), which leads to an enantiomerically enriched
primary amine salt B along with the corresponding
Hantzsch pyridine. Subsequently, the amine salt undergoes
a counterion exchange with HCl to provide product salt 4a.
A plausible transition state similar to TS rationalizes the
MeO
4k
4l
4j
92%, e.r. = 99:1d
85%, e.r. = 97.5:2.5a,d,e
73%, e.r. = 97:3
NH3Cl
NH3Cl
NH3Cl
S
4n
4o
4m
85%, e.r. = 97.5:2.5f,g
83%, e.r. = 98:2a,d
87%, e.r. = 99:1
Scheme 2 Exploration of the substrate scope. Reactions were per-
formed on a 0.25 mmol scale. The e.r. was determined by HPLC analysis
of the isolated HCl salt of amine products. a 5 mol% of catalyst. b Slower
addition of imine HCl salt 1c in MeCy, at 15 °C, 8 h. c 48 h. d 96 h. e Reac-
tion was performed in MTBE–CHCl3. f 72 h. g At 10 °C.
HCl salt afforded amine HCl salt product 4m in good yield
and with an e.r. of 99:1. Interestingly, phenylethyl-substi-
tuted N–H imine HCl salt 1n was reduced at 10 °C in 85%
yield with an e.r. of 97.5:2.5. A heterocyclic substrate, thio-
phene derivative 1o, efficiently underwent the reduction to
afford the corresponding amine HCl salt 4o in 83% yield and
with an e.r. of 98:2.
To illustrate the practicality of our methodology, imine
HCl salt 1b was reduced on a 5 gram scale by employing
only 0.5 mol% (188 mg) of DSI-3c to afford the desired
amine HCl salt 4b in 95% yield and with an e.r. of 99:1 with-
out requiring column chromatography (Scheme 3). Catalyst
DSI-3c can be recovered in 76% yield via flash column chro-
matography followed by acidification.
Scheme 3 Scale-up reaction with a chromatography-free protocol
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
V. N. Wakchaure et al.
Letter
Synlett
transfer of the axial chirality of catalyst DSI-3c to the final
product. Thus, -stacking interactions favor the aromatic
substituent of the iminium ion substrate closer to the cata-
lyst leading to the stereoselective addition of hydride to the
re-face of the iminium ion.
In summary, we have developed an asymmetric Brønst-
ed acid catalyzed reduction of N–H imine hydrochloride
salts. The reaction is catalyzed by a disulfonimide catalyst,
uses a Hantzsch ester as the hydrogen source, and provides
facile access to several hydrochloride salts of primary
amines in good yields and excellent enantioselectivities.
Mechanistic studies suggest a bifunctional activation mode
of our DSI catalyst. The use of iminium salts in asymmetric
Brønsted acid catalyzed transformations suggests potential
utility of our approach in many other useful processes.
Funding Information
Generous support from the Max-Planck-Gesellschaft, the Deutsche
Forschungsgemeinschaft (Leibniz Award to B.L. and Cluster of Excel-
lence RESOLV, Grant No. EXC 1069), and the European Research Coun-
cil (Advanced Grant ‘C–H Acids for Organic Synthesis, CHAOS’) are
gratefully acknowledged. C.O. also acknowledges Alexander von
Humboldt Foundation and Bayer Science & Education Foundation for
the Humboldt-Bayer Fellowship for Postdoctoral Researchers.
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Acknowledgment
We thank the technicians of our group, and the MS, GC, HPLC, and
NMR groups of the Max-Planck-Institut für Kohlenforschung, espe-
cially J. Lingnau for their excellent service. Finally, we gratefully ac-
knowledge our lab colleagues for their suggestions via internal Crowd
Reviewing, especially J. L. Kennemur.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706413.
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References and Notes
(1) For selected reviews, see: (a) Terada, M. Chem. Commun. 2008,
4097. (b) Kampen, D.; Reisinger, C. M.; List, B. Top. Curr. Chem.
2010, 291, 395. (c) Terada, M. Synthesis 2010, 1929. (d) Akiyama,
T. In Science of Synthesis: Asymmetric Organocatalysis, Vol. 2;
Maruoka, K., Ed.; Thieme: Stuttgart, 2012, 169. (e) Akiyama, T.;
Mori, K. Chem. Rev. 2015, 115, 9277.
(2) Nugent, T. C. In Chiral Amine Synthesis: Methods, Developments
and Applications; Nugent, T. C., Ed.; Wiley-VCH: Weinheim,
2010.
O
O
5a: R = Cl
5b: R = H
5c: R = Me
5d: R = NO2
R
O
S
O O
O
O
S
O O O
S
S
S
NH
N
H
N
H
CF3
R
O
6
7
b
NH3Cl
NH2Cl
(3) For selected recent reviews on asymmetric reduction of imines
and reductive amination of ketones, see: (a) Nugent, T. C.; El-
Shazly, M. Adv. Synth. Catal. 2010, 352, 753. (b) Fleury-Bregeot,
N.; de la Fuente, V.; Castillon, S.; Claver, C. ChemCatChem 2010,
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111, 1713. (d) Wang, C.; Xiao, J. Top. Curr. Chem. 2014, 343, 261.
(e) Tang, W.; Xiao, J. Synthesis 2014, 46, 1297. (f) Morisaki, K.;
Morimoto, H.; Ohshima, T. ACS Catal. 2020, 10, 6924. For
selected recent examples of TM-catalyzed asymmetric reduc-
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Hermsen, M.; Wysocki, J.; Ernst, M.; Rominger, F.; Trapp, O.;
Hashmi, A. S. K.; Schaefer, A.; Comba, P.; Schaub, T. J. Am. Chem.
Soc. 2018, 140, 355. (h) Tan, X.; Gao, S.; Zeng, W.; Xin, S.; Yin, Q.;
Zhang, X. J. Am. Chem. Soc. 2018, 140, 2024.
Ph
X
Ph
4a
1a
H
X
[DSI-3]
HCl
HCl
CF3
NH3
NH2
X
CF3
F3C
Ph
N
Ph
A
B
F3C
H
O
S
E
E
E
E
E
N
O
H
H
N
N
E
H
H
S
H
N
O
F3C
O
[π-stacking]
[H-bonding]
[acidity]
[bifunctionality]
TS
F3C
(4) (a) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int. Ed.
2005, 44, 7424. (b) Wakchaure, V. N.; Nicoletti, M.; Ratjen, L.;
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Leutzsch, M.; List, B. Angew. Chem. Int. Ed. 2015, 54, 11852.
(5) For selected examples of other organocatalytic asymmetric
imine reductions and reductive aminations, see: (a) Storer, R. I.;
Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006,
CF3
CF3
Scheme 4 Mechanism. a Overall rate to 50% yield in the reduction of
1a using catalysts with different pKa (values in CH3CN, see Supporting
Information for further details). b Proposed catalytic cycle along with a
stereochemical model of the transition state between the ion pair A
t
and Hantzsch ester 2 (E = CO2 Bu).
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

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V. N. Wakchaure et al.
Letter
Synlett
128, 84. For selected examples of organocatalytic asymmetric
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Phillips, A. M.; Pombeiro, A. J. L. Org. Biomol. Chem. 2017, 15,
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see: (a) Malkov, A. V.; Stončius, S.; MacDougall, K. N.; Mariani,
A.; McGeoch, G. D.; Kočovský, P. Tetrahedron 2006, 62, 264.
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(7) For asymmetric imine reductions using catecholborane, see:
Enders, D.; Rembiak, A.; Seppelt, M. Tetrahedron Lett. 2013, 54,
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(8) For metal-catalyzed N–H imine hydrochloride salt reduction,
see: (a) Zhao, Q.; Wen, J.; Tan, R.; Huang, K.; Metola, P.; Wang,
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(b) Hou, G.; Tao, R.; Sun, Y.; Zhang, X.; Gosselin, F. J. Am. Chem.
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Davies, I. W.; Zhang, X. J. Am. Chem. Soc. 2009, 131, 9882. For
metal-catalyzed unprotected -enamino esters reduction, see:
(d) Hou, G.; Li, W.; Ma, M.; Zhang, X.; Zhang, X. J. Am. Chem. Soc.
2010, 132, 12844.
(9) For organocatalytic ortho-hydroxyaryl alkyl and ortho-hydroxy-
benzophenone N–H imine reduction, see: (a) Nguyen, T. B.;
Bousserouel, H.; Wang, Q.; Gueritte, F. Org. Lett. 2010, 12, 4705.
(b) Nguyen, T. B.; Wang, Q.; Gueritte, F. Chem. Eur. J. 2011, 17,
9576. For enantioselective reduction of aryl trifluoromethyl-
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(c) Gosselin, F.; O'Shea, P. D.; Roy, S.; Reamer, R. A.; Chen, C.-Y.;
Volante, R. P. Org. Lett. 2005, 7, 355. For a Lewis base catalyzed
asymmetric reduction of unprotected -enamino esters with
trichlorosilane, see: (d) Ye, J.; Wang, C.; Chen, L.; Wu, X.; Zhou,
L.; Sun, J. Adv. Synth. Catal. 2016, 358, 1042. For the nucleophilic
reaction to CF3NH ketimines catalyzed by Brønsted acid, see:
(e) Sawa, M.; Morisaki, K.; Kondo, Y.; Morimoto, H.; Ohshima, T.
Chem. Eur. J. 2017, 23, 17022. (f) Yonesaki, R.; Kondo, Y.; Akkad,
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Eur. J. 2018, 24, 15211. (g) Miyagawa, M.; Yoshida, M.; Kiyota, Y.;
Akiyama, T. Chem. Eur. J. 2019, 25, 5677. For an example of using
of N–H imine hydrochloride salts as in situ imine precursor in
catalytic asymmetric additions, see: (h) Jang, H.; Romiti, F.;
Torker, S.; Hoveyda, A. H. Nat. Chem. 2017, 1269.
(10) Wakchaure, V. N.; List, B. Angew. Chem. Int. Ed. 2016, 55, 15775.
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Org. Biomol. Chem. 2017, 15, 6943.
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DOI: 10.1055/s-0040-1707129.
(15) General Procedure for the Asymmetric Reduction of N–H
Imine Hydrochloride Salts
An oven-dried 10 mL vial was charged with the hydrochloride
salt of imine 1 (0.25 mmol), Hantzsch ester 2 (108.3 mg, 0.35
mmol, 1.4 equiv), disulfonimide DSI-3c, freshly activated MS 5Å
(250 mg), and a magnetic stirring bar at RT. Then 7.5 mL (0.033
M) of MTBE–MeCy (MTBE–CHCl3 in case of 1l) was added under
an argon atmosphere. The mixture was then subjected to the
appropriate reaction time and temperature. The reaction
mixture was filtered over Celite, washed with isohexane (40
mL), and isohexane–MTBE (1:1, 40 mL) to remove the neutral
compounds. The hydrochloride salt of the desired amine
product 4 was then collected in >99% purity (by 1H NMR analy-
sis) by washing with 3% MeOH in CH2Cl2 (60 mL) and evaporat-
ing the filtrate under reduced pressure. The enantiomeric ratio
of products 4 was determined by HPLC after benzoylation fol-
lowing a standard procedure. Crude enantiomeric ratios were
determined after subjecting the reaction mixture with sat.
NaHCO3 solution, extracting the free amine product with MTBE,
followed by benzoylation and HPLC analysis.
(S)-1-[4-(tert-Butyl)phenyl]ethan-1-aminium Chloride (4b)
Prepared according to the general procedure using DSI-3c (7.98
mg, 2.0 mol%, 0.02 equiv) in MTBE–MeCy (1:1) at RT for 24 h
and obtained as colorless solid (43.25 mg, 81%, e.r. = 99.5:0.5,
crude reaction e.r. = 99.5:0.5). 1H NMR (500 MHz, CDCl3):  =
8.58 (br s, 3 H), 7.46–7.27 (m, 4 H), 4.30–4.20 (m, 1 H), 1.55 (d,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

F
V. N. Wakchaure et al.
Letter
Synlett
J = 6.8 Hz, 3 H), 1.21 (s, 9 H). 13C NMR (126 MHz, CDCl3):  =
(16) Additionally, when imine salt 1a was dissolved in CHCl3 and fil-
tered through an HPLC filter to ensure complete absence of
insoluble salt, reduction under completely homogeneous condi-
tions proceeded efficiently and with high enantioselectivity
(e.r. = 93:7).
(17) (a) Nelson, H. M.; Patel, J. S.; Shunatona, H. P.; Toste, F. D. Chem.
Sci. 2015, 6. 170. (b) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat.
Chem. 2012, 4, 603.
151.8, 135.4, 126.8, 126.0, 51.5, 34.7, 31.4, 20.8. HRMS (ESI):
m/z calcd for
C12H20N [M –
Cl]+: 178.159060; found:
178.159024. The enantiomeric ratio was determined by deri-
vatization to the corresponding benzamide by HPLC analysis
using Daicel Chiralpak OD-3, n-heptane–IPA = 80:20, flow
rate = 1.0 mL/min, 25 °C,  = 220 nm, tR = 3.13 min (minor) and
tR = 4.60 min (major). []D25 –16.0° (c 0.63, CH2Cl2).
(18) See the Supporting Information for NMR studies on the specia-
tion of the catalyst with the substrates and the products under
the reaction conditions.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F