Asymmetric Stepwise Reductive Amination of Sulfonamides, Sulfamates, and a Phosphinamide by Nickel Catalysis

Article abstract of DOI:10.1002/anie.201809930

Asymmetric reductive amination of poorly nucleophilic sulfonamides was realized in the presence of nickel catalysts and titanium alkoxide. A wide range of ketones, including enolizable ketones and some biaryl ones, were converted into sulfonamides in excellent enantiomeric excess. The cyclization of sulfamates and intermolecular reductive amination of a diarylphosphinamide were also successful. Formic acid was used as a safe and economic surrogate of high-pressure hydrogen gas.

Full text of DOI:10.1002/anie.201809930

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Asymmetric Stepwise Reductive Amination of Sulfonamides,
Sulfamates and a Phosphinamide via Nickel Catalysis
Authors: Jianrong Steve Zhou, Xiaohu Zhao, Haiyan Xu, and Xiaolei
Huang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809930
Angew. Chem. 10.1002/ange.201809930
Link to VoR: http://dx.doi.org/10.1002/anie.201809930
http://dx.doi.org/10.1002/ange.201809930

10.1002/anie.201809930
Angewandte Chemie International Edition
COMMUNICATION
Asymmetric Stepwise Reductive Amination of Sulfonamides,
Sulfamates and a Phosphinamide via Nickel Catalysis
Xiaohu Zhao, Haiyan Xu, Xiaolei Huang and Jianrong Steve Zhou*
Abstract: asymmetric reductive amination of poorly
nucleophilic sulfonamides is realized in the presence of
nickel catalysts and titanium alkoxide. A wide range of
enolizable ketones, including some dialkyl and biaryl ones,
were converted to sulfonamides in excellent enantiomeric
excess. Cyclization of sulfamates and intermolecular
reductive amination of a diarylphosphinamide were also
successful. Formic acid was used as a safe and economic
surrogate of high-pressure hydrogen gas.
with more nucleophilic sulfinamides followed by oxidation.[17]
In a typical example, Zhang et al. reported that 1 mol%
palladium/TangPhos catalyzed hydrogenation of pre-formed
N-tosyl ketimines, although 75 bar of hydrogen pressure was
required.[17a]
Similarly,
simple
condensation
of
diarylphosphinamides and ketones has remained difficult.[18]
In asymmetric hydrogenation,[11c,17b] borohydride reduction[19]
and hydrosilylation of these ketimines,[20] they were prepared
beforehand via
a moderately-yielding condensation of
oximes and chlorodiarylphosphines.[21] Notably, high
pressure of hydrogen gas (40-75 bar) was needed in
hydrogenation of the two types of ketimines.
Chiral alkylamines are commonly structural elements in
modern medicines and their enentioselective synthesis has
attracted significant research interest.[1] Sulfonamides, in
particular, are common pharmacophores and are considered
to be useful isosteres of carboxylic acids and carboxamides
in drug discovery.[2] In fact, the sulfonamide family of
antibiotics are the first family of antibiotics that were used
systematically.[3] Sulfonamides are also present in many
other medicines, such as antiviral, anticancer and
antiinflammatory agents.[4] Moreover, chiral sulfonamides
containing α-stereogenic centers have also emerged
recently in medicine, for example, ramatroban, a drug for the
treatment of coronary artery disease and asthma[5] and MK-
7246, a drug candidate targeting respiratory diseases.[6]
Other chiral sulfonamide drugs target cancers,[7] Type II
diabetes[8] and Alzheimer’s disease[9] (Figure 1).
F
F
H
H
N
N
S
O
N
S
O
O
O
N
CO2H
Ramatroban
thromboxane and DP2 receptor antagonist
(coronary artery disease and ashma)
O
CO2H
MK-7246
CRTH2 antagonist
(respiratory diseases)
NH
O
Ph
O
H
Me
O
N
O
S
N
O
O
N
S
N
H
H2N
O
H
Me
NH
hepsin inhibitor
(cancer)
dUTPase inhibitor
(breast cancer)
CF3
O
O
O
S
F
Cl
NH
H2N
O
N
S
S
O
O
N
O
O
N
hGK-hGKRP discruptor
lowering blood glucose
(Type II diabetes)
Cl
Avagacestat (BMS-708163)
γ−secretase inhibitor
(Alzheimer's disease)
Compared to asymmetric hydrogenation of pre-formed
ketimines and enamines using rare noble metal catalysts[10]
and abundant 3d metal catalysts,[11] reductive amination of
ketones and amines avoids the isolation and purification of
ketimines, some of which are unstable during purification and
storage.[12] To date, most late metal-catalyzed[13] or
organocatalytic[14] methods for asymmetric reductive
amination are limited to arylamines and acylhydrazines,
which undergo facile condensation with ketones to form
ketimines in the presence of acid catalysts and molecular
sieves. For instance, in 2016 we reported nickel-catalyzed
asymmetric reductive amination using arylamines and
benzhydrazide.[15] Reductive amination using amines of
attenuated nucleophilicity, such as sulfonamides and
phosphinamides, still remains a challenge, especially when
enolizable ketones are used.[16] Thus, in existing Rh- and Pd-
catalyzed asymmetric hydrogenation, for example, N-sulfonyl
ketimine needed to be prepared first, by condensing ketones
Figure 1. Chiral sulfonamides in medicines
NiCl2(DME) 5 mol%
bisphosphine 6 mol%
Ti(OEt)4
O
NHTs
TsNH2
toluene
120 oC, 24 h
Ph
Me
HCO2H/Et3N 2:2, 3Å MS
CF3CH2OH, 80 oC, 48 h
Ph
Me
2a
1a 1.5 equiv
R
R
R
R
t-Bu
P
P
H
P
P
P
R
R
R
R
P
H
t-Bu
(S)-BPE
(R)-DuPhos
(S)-Binapine
R = Ph 62%, 91% ee
R = i-Pr 80%, 82% ee
R = Me 46%, 66% ee
R = Et 30%, 67% ee
87%, 93% ee
Me
P
Me
H
N
N
P
t-Bu
t-Bu
t-Bu
t-Bu
P
P
H
P
P
t-Bu
t-Bu
Me
Me
(R)-QuinoxP*
(R)-BenzP*
(1S)-TangPhos
73%, 59% ee
73%, 91% ee
81%, 89% ee
Me
Me
[*]
Dr. X. Zhao, Dr. H. Xu, Dr. X. Huang and Prof. Dr. J. S. Zhou
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, 21 Nanyang Link, SPMS-CBC-
06-06, Singapore 637371
H
PCy2
PCy2
PtBu2
PCy2
Fe
Fe
P
P
H
t-Bu
t-Bu
(R,Sp)-CyPF-Cy
78%, 73% ee
(R,Sp)-CyPF-t-Bu
79%, 80% ee
(1S)-DuanPhos
76%, 75% ee
E-mail: jrzhou@ntu.edu.sg
Scheme 1. The effect of chiral bisphosphines on reductive amination
of acetophenone and p-tosylamine.
Supporting information for this article is available on the WWW
under http://www.angewandte.org.
This article is protected by copyright. All rights reserved.

10.1002/anie.201809930
Angewandte Chemie International Edition
COMMUNICATION
(a) Products from (hetero)aryl ketones
Initially, we attempted nickel-catalyzed reductive
amination of acetophenone 1a and p-tosylamine using formic
acid under various condensation conditions (Scheme 1).
Often we observed facile ketone reduction, self-aldol
condensation of acetophenone to form an enone. The latter
also underwent nonselective reduction in the reaction
mixture. Eventually, we attempted the condensation using
titanium ethoxide in refluxing toluene,[16] which led to the
desired ketimine in good yield. Subsequent treatment of the
N-sulfonyl ketimine[17] with a nickel catalyst ligated with
binapine,[22] formic acid and triethylamine afforded
sulfonamide 2a in 93% yield and 93% ee. Notably, when this
model reaction was conducted without prior formation of the
ketimine, 2a was still obtained in 87% yield in the presence
of Ti(OEt)4. A detailed catalyst screening revealed that
several other chiral bisphosphines also provided >90% ee for
this hydrogenation, including Ph-BPE, QuinoxP* and BenzP*
(see Scheme 1). We also tested catalytic performance of
[(S)-binapine]NiCl2 complex, which was similar to the catalyst
cocktail described in Scheme 1. When 1, 2 and 5 mol%
nickel complex was used, the yield of 2a was 43, 65 and
82% after 48 h, respectively.
NiCl2(DME) 5 mol%
NHTs
Me
Ti(OEt)4
O
(S)-binapine 6 mol%
TsNH2
Ph
toluene
120 oC, 24 h
Ph
Me
HCO2H/Et3N 2:2
CF3CH2OH, 3Å MS
80 oC, 48 h
2a 87%, 93% ee
1a 1.5 equiv
NHTs
F
NHTs
Me
Me NHTs
NHTs
Me
Me
Me
F
Y
2d 86% 94% ee
2b Y = Me 84%, 96% ee
2c Y = OMe 89%, 93% ee
2f 81%, 93% ee
2e 91%, 95% ee
NHTs
Me
NHTs
NHTs
NHTs
Me
O
O
Me
MeO
O
Me
Me
O
2g 80%, 94% ee
2h 85%, 95% ee
2i 89%, 96% ee
2j 88%, 90% ee
NHTs
Me
NHTs
Me
NHTs
Me
NHTs
Me
O
2l 84%, 96% ee
2n 78%, 97% ee
2m 86%, 96% ee
2k 89%, 95% ee
NHTs
NHTs
Et
NHTs
NHTs
S
S
Me
Me
With the optimal conditions using the nickel/binapine
catalyst in hand, we explored the scope of ketones in
reaction of p-tosylamine (Scheme 2a). Aryl ketones with
different electronic properties (2b-j) and heteroaryl ketones
(2n-p) gave the desired products in good yields and >95%
ee values. Interestingly, both cyclic 1-indanone and 1-
tetralone provided products (2r-s) in almost perfect ees. In
the reaction of indanone, a moderate yield of 2r resulted,
owing to facile aldol condensation of 1-indanone.
Unfortunately, titanium ethoxide failed to promote
2o 68%, 97% ee
2p 81%, 96% ee
[X-ray structure]
2r 58%, 99% ee
2q 91%, 82% ee
NHTs
NHTs
2t 80%, 84% ee
2s 89%, 99% ee
(b) Products from biaryl ketones
NHTs
NHTs
NHTs
NHTsMe
S
S
Ph
Ph
Ph
condensation
of
highly
electron-deficient
1,1,1-
Ph
trifluoroacetophenone with tosylamine.
2w 82%, 90% ee
2u 85%, 90% ee
[X-ray structure]
2v 90%, 90% ee
2x 87%, 90% ee
Excitingly, we found that some biaryl ketones furnished
the corresponding tosylamines (2u-2x) in excellent ee values
(Scheme 2b).[23] On the ketimines, to our delight, the
nickel/binapine catalyst successfully differentiated a phenyl
ring and a larger o-tolyl or 1-naphthyl group (2u-2v).
Furthermore, the same catalyst also discriminated a phenyl
ring versus thiophene and benzothiophene (2w-2x). The
absolute configuration of product 2u was determined by X-
ray diffractional analysis.[24]
(c) Products from aliphatic ketones
NHTs
NHTs
NHTs
Me
Me
Me
Me
NHTs
Me
Me
NHTs
Me
Me
Me
Me
Me
Me
Me
2y
2z
2aa
84%, 93% ee
2ab
84%, 90% ee
2ac
84%, 73% ee
88%, 97% ee
79%, 95% ee
with (S)-binapine
with (R)-QuinoxP*
with (R,Sp)-CyPF-Cy
Scheme 2. Reductive amination of different types of ketones with p-
tosylamine.
In reactions of common aliphatic ketones (Scheme 2c),
we found that nickel catalysts can successfully provide >90%
ee, when a suitable bisphosphine was used judiciously. Thus,
methyl ketones bearing t-butyl, cyclohexyl, sec-butyl and
isopropyl groups (2y-2ab) were hydrogenated in excellent ee
by nickel catalysts of binapine, Josiphos CyPF-Cy and
QuinoxP*, respectively. However, asymmetric reductive
amination of ethyl methyl ketone (2ac) still remained a
significant challenge as expected (73% ee).
We then investigated the scope of sulfonamides using
the nickel/binapine catalyst under conditions described in
Scheme 2. The results are summarized in Scheme 3. The
sulfonamides tolerated large ortho groups on aryl rings (3d-e)
and strongly electron-donating groups (3g and 3i). However,
many arenesulfonamides with highly electron-deficient
arenes failed to condense with acetophenone, except that 4-
fluorobenzenesulfonamide still reacted and gave the desired
amine (3j) in 60% yield. Notably, thiophene (3k-l), a
cyclopropyl ring (3o) and aliphatic groups (3m, 3n and 3p)
can be present on sulfonamides. In cases that afforded
desired products (3m-n) in moderate yields, self-aldol
This article is protected by copyright. All rights reserved.

10.1002/anie.201809930
Angewandte Chemie International Edition
COMMUNICATION
O
S
condensation of acetophenone accounted for most of the
remaining material. Unfortunately, the reaction of bulky t-
butylsulfonamide with acetophenone resulted in only 10%
yield of the target product.
H
O
NiCl2(DME) 5 mol%
(R,R)-Ph-BPE 6 mol%
H
O
N
N
.
cat. Ti(OEt)4
S
O
NH2
O
NH
HCO2H Et3N 5:2
CF3CH2OH, 3Å MS
80 oC, 48 h
toluene
110 oC, 4 h
Me
Me
93%, 95% ee
Me
Examples
Me
O
Me
O
O
H
H
O
H
N
H
N
N
N
S
O
S
O
S
O
Me
S
SO2
SO2
HN
Ph
HN
Ph
HN
Ph
SO2
NH
HN
Ph
SO2
NH
Me
O
Me
NH
NH
Ph
Me
Me
Me
Me
c-Hex
3b 81%, 90% ee
3a 80%, 91% ee
3c 75%, 90% ee
3d 70%, 94% ee
i-Pr
94%, 96% ee
Et
92%, 93% ee
95%, 96% ee
95%, 96% ee
iPr
O
iPr
tBu
OMe
O
S
O
S
Scheme 4. Asymmetric synthesis of benzosulfamates.
O
S
S
HN
HN
O
HN
O
HN
O
iPr
O
Ph
Me
Ph
Me
Ph
Me
NiCl2(DME) 5 mol%
Ph
Me
O
P
O
NHP(O)Ph2
Ti(OEt)4
(1S)-TangPhos 6 mol%
3g 90%, 94% ee
3h 60%, 95% ee
3f 73%, 93% ee
3e 80%, 95% ee
(a)
Ph
Ph
H2N
Ph
Me
Ph
Me
HCO2H/Et3N 2:2
CF3CH2OH, 3Å MS
80 oC, 48 h
toluene
120 oC, 24 h
O
O
1.5 equiv
6a 82%, 75% ee
F
O
S
S
S
S
HN
O
S
HN
O
O
S
O
S
O
HN
O
HN
O
NiCl2(DME) 10 mol%
O
NHP(O)Ph2
O
P
Ph
Me
Me
Ti(OEt)4
(1S)-TangPhos 12 mol%
Ph
Me
(b)
3l 82%, 90% ee
[X-ray structure]
3j 60%, 92% ee
Ph
Ph
3i 76%, 94% ee
3k 75%, 87% ee
H2N
HCO2H/Et3N 2:2
CF3CH2OH, 3Å MS
100 oC, 60 h
toluene
120 oC, 24 h
1.5 equiv
MeO
O
O
6b 80%, 94% ee
O
S
O
S
O
O
HN
HN
Me
S
Ph
S
HN
Ph
3m 41%, 95% ee
NHP(O)Ph2
F
O
HN
O
Me
Me
NHP(O)Ph2
NHP(O)Ph2
Me
Me
Ph
Me
3n 61%, 97% ee
3o 70%, 96% ee
3p 84%, 96% ee
Me
6d 75%, 91% ee
6c 83%, 92% ee
6e 77%, 93% ee
GK-GKRP disrupters
O
O
O
O
Scheme 5. Asymmetric reductive amination of ketones and
O
O
O
S
diphenylphosphinamide.
S
O
S
O
O
O
Cl HN
HN
HN
O
S
S
O
Gratifyingly, we discovered that stepwise reductive
amination with titanium ethoxide can be successfully
extended to diphenylphosphinamide without any problem.
For example, a nickel/TangPhos catalyst afforded product 6a
in 82% yield and 75% ee (Scheme 5a), while the
nickel/binapine catalyst only afforded the product in 30% ee.
To our delight, reductive amination of substituted 1-
tetralones afforded desired products 6b-e in greater than 90%
ee, even though a longer reaction time was needed (Scheme
5b). Of note, a similar reaction with indanone, however, led
mainly to self-aldol condensation.
3q 85%, 80% ee
[X-ray structure]
3r 84%, 90% ee
3s 74%, 96% ee
[X-ray structure]
Scheme 3. Asymmetric reductive amination of other sulfonamides (3a-p)
and synthesis of drug candidates (3q-s).
Furthermore, the nickel catalysis was successfully
applied to asymmetric synthesis of biarylmethylamines (3q-
s), which were identified to be promising candidates for the
treatment of Type II diabetes.[8] In particular, 3s is a disruptor
of human glucokinase and its regulatory protein at
nanomolar concentrations. In the two examples containing
benzothiophene rings, over 90% ee was achieved. We have
ascertained the absolute stereochemistry of 3q and 3s with
single crystal X-ray diffraction.[24]
The chiral N-tosylamines from the reductive amination
were readily transformed to other chiral building blocks
(Scheme 6). For example, the N-tosyl group of benzylamine
2a was easily converted into an N-Boc group (7a) after the
treatment of SmI2.[26] Moreover, biaryl sultam 7b was also
synthesized under an oxidative coupling condition with
AgOAc.[27] In a third example, 2a efficiently coupled with o-
bromobenzyl bromide in one pot to provide dibenzoazepine
7c.[28] No loss of enantiomeric purity was detected in all the
transformations herein. For biaryl 7b-c, only a single
atropoisomer was detected in solution by proton NMR
spectroscopy.
We also attempted intermolecular reductive amination of
ketones and sulfamates, but unfortunately sulfamates were
unstable towards titanium alkoxides and p-tosylic acid.
Luckily, we found that intramolecular condensation of
sulfamate 4a was readily catalyzed by p-tosylic acid, which
allowed us to prepare cyclized product 5a in one pot
(Scheme 4). Alternatively, 10 mol% of Ti(OEt)4 can be used
for the condensation to give almost identical results. From
catalyst screening, the nickel catalyst of Ph-BPE delivered
5a in excellent yield and 95% ee. The absolute configuration
of 5a was established by single-crystal X-ray diffraction.[24]
This stepwise procedure was readily applied to asymmetric
synthesis of other benzofused sulfamates.[25]
This article is protected by copyright. All rights reserved.

10.1002/anie.201809930
Angewandte Chemie International Edition
COMMUNICATION
NHTs
NHBoc
Me
Ahmad, R. Gildardo, A. Muhammad, Mini-Rev. Med. Chem. 2013,
13, 70.
SmI2, pyrrolidine
H2O, THF
(Boc)2O
(a)
Me
2a
2a 93% ee
[5] a) H. Sugimoto, M. Shichijo, T. Iino, Y. Manabe, A. Watanabe, M.
Shimazaki, F. Gantner, K. B. Bacon, J. Pharmacol. Exp. Ther.
2003, 305, 347; b) J. F. Royer, P. Schratl, J. J. Carrillo, R. Jupp,
J. Barker, C. Weyman-Jones, R. Beri, C. Sargent, J. A. Schmidt,
D. Lang-Loidolt, A. Heinemann, Eur. J. Clin. Invest. 2008, 38,
663.
[6] a) M. Gallant, C. Beaulieu, C. Berthelette, J. Colucci, M. A.
Crackower, C. Dalton, D. Denis, Y. Ducharme, R. W. Friesen, D.
Guay, F. G. Gervais, M. Hamel, R. Houle, C. M. Krawczyk, B.
Kosjek, S. Lau, Y. Leblanc, E. E. Lee, J.-F. Levesque, C. Mellon,
C. Molinaro, W. Mullet, G. P. O’Neill, P. O’Shea, N. Sawyer, S.
Sillaots, D. Simard, D. Slipetz, R. Stocco, D. Sørensen, V. L.
Truong, E. Wong, J. Wu, H. Zaghdane, Z. Wang, Bioorg. Med.
Chem. Lett. 2011, 21, 288; b) F. G. Gervais, N. Sawyer, R.
Stocco, M. Hamel, C. Krawczyk, S. Sillaots, D. Denis, E. Wong, Z.
Wang, M. Gallant, W. M. Abraham, D. Slipetz, M. A. Crackower,
G. P. O'Neill, Mol. Pharmacol. 2011, 79, 69.
[7] a) S. Miyahara, H. Miyakoshi, T. Yokogawa, K. T. Chong, J.
Taguchi, T. Muto, K. Endoh, W. Yano, T. Wakasa, H. Ueno, Y.
Takao, A. Fujioka, A. Hashimoto, K. Itou, K. Yamamura, M.
Nomura, H. Nagasawa, S. Shuto, M. Fukuoka, J. Med. Chem.
2012, 55, 5483; b) S. M. Pant, A. Mukonoweshuro, B. Desai, M.
K. Ramjee, C. N. Selway, G. J. Tarver, A. G. Wright, K. Birchall,
T. M. Chapman, T. A. Tervonen, J. Klefström, J. Med. Chem.
2018, 61, 4335.
[8] L. D. Pennington, M. D. Bartberger, M. D. Croghan, K. L.
Andrews, K. S. Ashton, M. P. Bourbeau, J. Chen, S. Chmait, R.
Cupples, C. Fotsch, J. Helmering, F.-T. Hong, R. W. Hungate, S.
R. Jordan, K. Kong, L. Liu, K. Michelsen, C. Moyer, N. Nishimura,
M. H. Norman, A. Reichelt, A. C. Siegmund, G. Sivits, S.
Tadesse, C. M. Tegley, G. Van, K. C. Yang, G. Yao, J. Zhang, D.
J. Lloyd, C. Hale, D. J. St. Jean, J. Med. Chem. 2015, 58, 9663.
[9] a) K. W. Gillman, J. E. Starrett, M. F. Parker, K. Xie, J. J.
Bronson, L. R. Marcin, K. E. McElhone, C. P. Bergstrom, R. A.
Mate, R. Williams, J. E. Meredith, C. R. Burton, D. M. Barten, J.
H. Toyn, S. B. Roberts, K. A. Lentz, J. G. Houston, R. Zaczek, C.
F. Albright, C. P. Decicco, J. E. Macor, R. E. Olson, ACS Med.
Chem. Lett. 2010, 1, 120; b) H. Nishioka, N. Tooi, T. Isobe, N.
Nakatsuji, K. Aiba, Sci. Rep. 2016, 6, 33427.
Et3N, DCM
7a 70%, 93% ee
Me
O
Me
Pd(OAc)2 10 mol%
KOt-Bu 20 mol%
O
S
O
O
S
(b)
NH
Me
NH
AgOAc 3 equiv
PivOH/AcOH 3:1
130 oC, 24 h
Me
7b 73%, 93% ee
2a 93% ee
Pd(OAc)2 10 mol%
PPh3 20 mol%
NHTs
Me
NTs
Me
Br
Br
(c)
Cs2CO3, dioxane
110 oC, 16 h
2a 93% ee
7c 71%, 93% ee
Scheme 6. Product transformation.
In conclusion, we developed
a
nickel-catalyzed
asymmetric reductive amination of sulfonamides for the first
time. A diverse set of ketones, including some biaryl ketones
and aliphatic ketones, reacted to afford chiral sulfonamides
in excellent ees. A similar stepwise procedure also proved
successful in asymmetric cyclization of sulfamates and
intermolecular reductive amination of a diarylphosphinamide.
Formic acid was used as safe, easy-to-handle source of
hydrogen, which helped avoid the use and handling of high-
pressure hydrogen gas, a safety hazard.
Acknowledgements
We thank Singapore GSK-EDB Trust Fund (2017 GSK-EDB
green and sustainable manufacturing award) and Singapore
A*STAR Science & Engineering Research Council (AME IRG
A1783c0010) for financial support. We thank Ben Ashley for
some initial experiments. XZ and HX contributed equally to the
experiments.
[10] Reviews: a) H.-U. Blaser, C. Malan, B. Pugin, F. Spindler, H.
Steiner, M. Studer, Adv. Synth. Catal. 2003, 345, 103; b) W.
Tang, X. Zhang, Chem. Rev. 2003, 103, 3029; c) N. B. Johnson,
I. C. Lennon, P. H. Moran, J. A. Ramsden, Acc. Chem. Res.
2007, 40, 1291; d) H. Shimizu, I. Nagasaki, K. Matsumura, N.
Sayo, T. Saito, Acc. Chem. Res. 2007, 40, 1385; e) W. Zhang, Y.
Chi, X. Zhang, Acc. Chem. Res. 2007, 40, 1278; f) C. Wang, B.
Villa-Marcos, J. Xiao, Chem. Commun. 2011, 47, 9773; g) J.-H.
Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011, 111, 1713; h) D. J.
Ager, A. H. M. de Vries, J. G. de Vries, Chem. Soc. Rev. 2012,
41, 3340; i) H.-U. Blaser, B. Pugin, F. Spindler, Top. Organomet.
Chem. 2012, 1; j) Z. Yu, W. Jin, Q. Jiang, Angew. Chem. Int. Ed.
2012, 51, 6060; Angew. Chem. 2012, 124, 6164; k) P. Etayo, A.
Vidal-Ferran, Chem. Soc. Rev. 2013, 42, 728; l) F. Foubelo, M.
Yus, Chem. Record 2015, 15, 907.
Conflict of interest
The authors declare no conflict of interest
Keywords: chiral alkylamines • nickel catalysis • reductive
amination • transfer hydrogenation • sulfonamides
[11] Examples: a) S. Zhou, S. Fleischer, K. Junge, S. Das, D.
Addis, M. Beller, Angew. Chem. Int. Ed. 2010, 49, 8121; Angew.
[1] Reviews: a) R. N. Salvatore, C. H. Yoon, K. W. Jung,
Tetrahedron 2001, 57, 7785; b) Chiral Amine Synthesis: Methods,
Developments and Applications (Ed.:T. C. Nugent), Wiley-VCH,
Weinheim, 2010.
[2] a) J.-Y. Winum, A. Scozzafava, J.-L. Montero, C. T. Supuran,
Med. Res. Rev. 2006, 26, 767; b) D. A. Smith, R. M. Jones, Curr.
Opin. Drug Discovery Dev. 2008, 11, 72.
[3] R. J. Anderson, P. W. Groundwater, A. Todd, A. J. Worsley,
"Sulfonamide Antibacterial Agents" in Antibacterial Agents, John
Wiley & Sons, Ltd, 2012, pp. 103.
[4]a) A. Scozzafava, T. Owa, A. Mastrolorenzo, C. T. Supuran, Curr.
Med. Chem. 2003, 10, 925; b) C. T. Supuran, A. Casini, A.
Scozzafava, Med. Res. Rev. 2003, 23, 535; c) S. Syed Shoaib
Chem. 2010, 122, 8198; b)
1 mol% Fe-catalyzed transfer
hydrogenation of N-tosyl and N-phosphinyl ketimines using
isopropanol: A. A. Mikhailine, M. I. Maishan, R. H. Morris, Org.
Lett. 2012, 14, 4638; c) W. Zuo, A. J. Lough, Y. F. Li, R. H.
Morris, Science 2013, 342, 1080; d) P. O. Lagaditis, P. E. Sues,
J. F. Sonnenberg, K. Y. Wan, A. J. Lough, R. H. Morris, J. Am.
Chem. Soc. 2014, 136, 1367; e) L.-Q. Lu, Y. Li, K. Junge, M.
Beller, J. Am. Chem. Soc. 2015, 137, 2763; f) R. H. Morris, Acc.
Chem. Res. 2015, 48, 1494; g) H. Xu, P. Yang, P. Chuanprasit,
H. Hirao, J. Zhou, Angew. Chem. Int. Ed. 2015, 54, 5112; Angew.
Chem. 2015, 127, 5201; h) R. Bigler, A. Mezzetti, Org. Process
Res. Dev. 2016, 20, 253; i) Z. Zhang, A. Butt Nicholas, M. Zhou,
D. Liu, W. Zhang, Chin. J. Chem. 2018, 36, 443.
This article is protected by copyright. All rights reserved.

10.1002/anie.201809930
Angewandte Chemie International Edition
COMMUNICATION
[12] Reviews: a) T. C. Nugent, M. El-Shazly, Adv. Synth. Catal.
2010, 352, 753; b) C. Wang, J. Xiao, Top. Curr. Chem. 2014, 343,
261.
[13] Examples: a) H.-U. Blaser, Adv. Synth. Catal. 2002, 344, 17;
b) R. Kadyrov, T. H. Riermeier, Angew. Chem. Int. Ed. 2003, 42,
5472; Angew. Chem. 2003, 115, 5630; c) G. D. Williams, R. A.
Pike, C. E. Wade, M. Wills, Org. Lett. 2003, 5, 4227; d) C. Li, B.
Villa-Marcos, J. Xiao, J. Am. Chem. Soc. 2009, 131, 6967; e) L.
Rubio-Pérez, F. J. Pérez-Flores, P. Sharma, L. Velasco, A.
Cabrera, Org. Lett. 2009, 11, 265; f) D. Steinhuebel, Y. Sun, K.
Matsumura, N. Sayo, T. Saito, J. Am. Chem. Soc. 2009, 131,
11316; g) B. Villa-Marcos, C. Li, K. R. Mulholland, P. J. Hogan, J.
Xiao, Molecules 2010, 15, 2453; h) N. A. Strotman, C. A. Baxter,
K. M. J. Brands, E. Cleator, S. W. Krska, R. A. Reamer, D. J.
Wallace, T. J. Wright, J. Am. Chem. Soc. 2011, 133, 8362; i) M.
Chang, S. Liu, K. Huang, X. Zhang, Org. Lett. 2013, 15, 4354; j)
S. Zhou, S. Fleischer, H. Jiao, K. Junge, M. Beller, Adv. Synth.
Catal. 2014, 356, 3451; k) H. Huang, X. Liu, L. Zhou, M. Chang,
X. Zhang, Angew. Chem. Int. Ed. 2016, 55, 5309; Angew. Chem.
2016, 128, 5395.
[14] Examples: a) M. Rueping, E. Sugiono, C. Azap, T.
Theissmann, M. Bolte, Org. Lett. 2005, 7, 3781; b) S. Hoffmann,
M. Nicoletti, B. List, J. Am. Chem. Soc. 2006, 128, 13074; c) R. I.
Storer, D. E. Carrera, Y. Ni, D. W. C. MacMillan, J. Am. Chem.
Soc. 2006, 128, 84; d) Q. Kang, Z.-A. Zhao, S.-L. You, Adv.
Synth. Catal. 2007, 349, 1657; e) G. Li, Y. Liang, J. C. Antilla, J.
Am. Chem. Soc. 2007, 129, 5830; f) C. Zhu, T. Akiyama, Org.
Lett. 2009, 11, 4180; g) V. N. Wakchaure, J. Zhou, S. Hoffmann,
B. List, Angew. Chem. Int. Ed. 2010, 49, 4612; Angew. Chem.
2010, 122, 4716.
[15] P. Yang, L. H. Lim, P. Chuanprasit, H. Hirao, J. Zhou, Angew.
Chem. In. Ed. 2016, 55, 12083; Angew. Chem. 2016, 128, 12262.
[16] Ketimine condensation under microwave irradiation: P. Ortiz, J.
F. Collados, S. R. Harutyunyan, Eur. J. Org. Chem. 2016, 2016,
1247.
[17] a) Hydrogenation of N-tosyl ketimines by 1 mol% Rh or Pd
catalyst of TangPhos: Q. Yang, G. Shang, W. Gao, J. Deng, X.
Zhang, Angew. Chem. Int. Ed. 2006, 45, 3832; Angew. Chem.
2006, 118, 3916; b) hydrogenation of N-tosyl and N-
diphenylphosphinyl ketimines by
2 mol% Pd catalysts of
SynPhos or SegPhos under 40 bar of H2: Y.-Q. Wang, S.-M. Lu,
Y.-G. Zhou, J. Org. Chem. 2007, 72, 3729.
[18] S. Pindi, P. Kaur, G. Shakya, G. Li, Chemi. Biol. & Drug
Design 2010, 77, 20.
[19] 1 mol% Co/bis-β-ketoiminate: T. Yamada, T. Nagata, K. D.
Sugi, K. Yorozu, T. Ikeno, Y. Ohtsuka, D. Miyazaki, T.
Mukaiyama, Chem. - Eur. J. 2003, 9, 4485.
[20] Examples: a) 1-6 mol% Cu/Segphos: B. H. Lipshutz, H.
Shimizu, Angew. Chem. Int. Ed. 2004, 43, 2228; Angew. Chem.
2012, 51, 6060; b) 3 mol% Re/CNbox: K. A. Nolin, R. W. Ahn, F.
D. Toste, J. Am. Chem. Soc. 2005, 127, 12462.
[21] B. Krzyżanowska, W. J. Stec, Synthesis 1982, 270.
[22] W. Tang, W. Wang, Y. Chi, X. Zhang, Angew. Chem. Int. Ed.
2003, 42, 3509; Angew. Chem. 2003, 115, 3633.
[23] a) G. Hou, R. Tao, Y. Sun, X. Zhang, F. Gosselin, J. Am.
Chem. Soc. 2010, 132, 2124; b) D. Kong, M. Li, G. Zi, G. Hou, Y.
He, J. Org. Chem. 2016, 81, 6640.
[24] CCDC 1837640 (2p), 1850983 (2u), 1860781 (3l), 1860786
(3q), 1860787 (3s) and 1837941 (5a) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre
via http://www.ccdc.cam.ac.uk/data_request/cif.
[25] 3 examples from 2 mol% Pd-catalyzed hydrogenation of pre-
formed benzofused ketimines under 40 bar of H2: Y.-Q. Wang,
C.-B. Yu, D.-W. Wang, X.-B. Wang, Y.-G. Zhou, Org. Lett. 2008,
10, 2071.
[26] T. Ankner, G. Hilmersson, Org. Lett. 2009, 11, 503.
[27] J. K. Laha, K. P. Jethava, N. Dayal, J. Org. Chem. 2014, 79,
8010.
[28] J. K. Laha, N. Dayal, R. Jain, K. Patel, J. Org. Chem. 2014, 79,
10899.
This article is protected by copyright. All rights reserved.

10.1002/anie.201809930
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
O
Reductive Amination
O
O
O
O
Xiaohu Zhao, Haiyan Xu, Xiaolei Huang
and Jianrong Steve Zhou
S
O
NiCl2(DME) 5 mol%
(S)-binapine 6 mol%
O
Cl HN
S
O
H2N
Cl
Ti(OEt)4
S
toluene
120 oC, 24 h
HCO2H/Et3N 2:2
O
S
CF3CH2OH, 3Å MS
80 oC, 48 h
Page – Page
74% yield, 96% ee
Asymmetric Stepwise Reductive
Amination of Sulfonamides, Sulfamates
and a Phosphinamide via Nickel
Catalysis
for treament of Type II diabetes
Intermolecular reductive amination of amines with attenuated nucleophilicity,
including sulfonamides, sulfamates and a phosphinamide, proceeds without the need of
isolating ketimines. Formic acid is used as a safe and easy-to-handle hydrogen source.
This article is protected by copyright. All rights reserved.