Transition-Metal-Free Hydrogen Autotransfer: Diastereoselective N-Alkylation of Amines with Racemic Alcohols

Article abstract of DOI:10.1002/anie.201905870

A practical method for the synthesis of α-chiral amines by alkylation of amines with alcohols in the absence of any transition-metal catalysts has been developed. Under the co-catalysis of a ketone and NaOH, racemic secondary alcohols reacted with Ellman's chiral tert-butanesulfinamide by a hydrogen autotransfer process to afford chiral amines with high diastereoselectivities (up to >99:1). Broad substrate scope and up to a 10 gram scale production of chiral amines were demonstrated. The method was applied to the synthesis of chiral deuterium-labelled amines with high deuterium incorporation and optical purity, including examples of chiral deuterated drugs. The configuration of amine products is found to be determined solely by the configuration of the chiral tert-butanesulfinamide regardless of that of alcohols, and this is corroborated by DFT calculations. Further mechanistic studies showed that the reaction is initiated by the ketone catalyst and involves a transition state similar to that proposed for the Meerwein–Ponndorf–Verley (MPV) reduction, and importantly, it is the interaction of the sodium cation of the base with both the nitrogen and oxygen atoms of the sulfinamide moiety that makes feasible, and determines the diastereoselectivity of, the reaction.

Full text of DOI:10.1002/anie.201905870

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Transition-Metal-Free Hydrogen Autotransfer: Diastereoselective
N-Alkylation of Amines with Racemic Alcohols
Authors: Miao Xiao, Xin Yue, Ruirui Xu, Weijun Tang, Dong Xue,
Chaoqun Li, Ming Lei, Jianliang Xiao, and Chao Wang
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.201905870
Angew. Chem. 10.1002/ange.201905870
Link to VoR: http://dx.doi.org/10.1002/anie.201905870
http://dx.doi.org/10.1002/ange.201905870

10.1002/anie.201905870
Angewandte Chemie International Edition
RESEARCH ARTICLE
Transition-Metal-Free Hydrogen Autotransfer: Diastereoselective
N-Alkylation of Amines with Racemic Alcohols
Miao Xiao,#[a] Xin Yue,#[b] Ruirui Xu,[a] Weijun Tang,[a] Dong Xue,[a] Chaoqun Li,[a] Ming Lei,*[b] Jianliang
Xiao,*[a,c] and Chao Wang*[a]
Abstract: A practical method for the synthesis of α-chiral amines via
alkylation of amines with alcohols in the absence of any transition
metal catalysts has been developed. Under the co-catalysis of a
ketone and NaOH, racemic secondary alcohols reacted with
Ellman’s chiral tert-butanesulfinamide via a hydrogen autotransfer
process to afford chiral amines with high diastereoselectivities (up to
> 99:1). Broad substrate scope and up to 10-gram scale production
of chiral amines were demonstrated. The method could be applied to
the synthesis of chiral deuterium-labelled amines with high
deuterium incorporation and optical purity, including examples of
chiral deuterated drugs. The configuration of amine products is
found to be determined solely by the configuration of the chiral tert-
butanesulfinamide regardless of that of alcohols, which is
corroborated by DFT calculations. Further mechanistic studies
showed that the reaction is initiated by the ketone catalyst and
involves a transition state similar to that proposed for the Meerwein-
Ponndorf-Verley (MPV) reduction and importantly, it is the interaction
of the sodium cation of the base with both the nitrogen and oxygen
atoms of the sulfinamide moiety that makes feasible, and determines
the diastereoselectivity of, the reaction.
Introduction
Chiral amines, particularly α-chiral primary amines, are arguably
the most important intermediates used in the synthesis of
pharmaceuticals, agrochemicals and specialty chemicals.[1]
Indeed, many drug molecules contain α-chiral amine moieties
(Figure 1). A clean method for accessing such primary amines
1w, 2]
would be asymmetric hydrogenation of imino species.[1v,
However, this remains challenging in terms of substrate scope
and catalyst efficiency, with only a few literature reports being
seen,[3] documenting the preparation of α-chiral primary amines
Figure 1. Drugs with α-chiral amine moieties and routes for the synthesis of α-
chiral amines.
with high enantioselectivity via catalytic hydrogenation or
transfer hydrogenation. Industrially, α-chiral amines have been
produced via resolution with chiral acids[4] and biocatalytic
asymmetric hydrogenation of C=N bonds to afford α-chiral
secondary amines.[1v, 1x, 2a-d, 6] An excellent example is seen in
transformation,[2e, 5] and there are also a few examples of
the industrial production of the herbicide (S)-metolachlor via the
asymmetric hydrogenation of an imine with an iridium catalyst at
80 bar H2, on a >10000 tonnes/year scale.[7] A disadvantage of
the hydrogenation method is the need for the usually-labile imine
precursors and high hydrogen pressure; the latter may not suit
routine fine chemical and pharmaceutical synthesis (Figure 1).
The direct asymmetric alkylation of amines with alcohols (or
amination of alcohols with amines) via a “borrowing hydrogen”
(or hydrogen autotransfer) strategy[8] is an attractive alternative
to access chiral amines. In 2004, Fujita, Yamaguchi and co-
workers reported the first diastereoselective amination of
alcohols with chiral amine substrates catalyzed by [Cp*IrCl2]2
(Figure 1),[9] which was later applied by Trudell and co-workers
in the synthesis of a natural product.[10] Williams and co-workers
also used a chiral amine substrate in a Ru catalyzed amination
of alcohols with retention of chirality in the product, albeit with no
[a]
M. Xiao, R. R. Xu, Prof. Dr. W. J. Tang, Prof. Dr. D. Xue, Prof. Dr. C.
Q. Li, Prof. Dr. J. L. Xiao, Prof. Dr. C. Wang
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry
of Education, School of Chemistry and Chemical Engineering,
Shaanxi Normal University, Xi’an, 710062, China
E-mail: c.wang@snnu.edu.cn
[b]
[c]
X. Yue, Prof. Dr. M. Lei
State Key Laboratory of Chemical Resource Engineering, Institute of
Computational Chemistry, College of Chemistry, Beijing University
of Chemical Technology, Beijing, 100029, China
E-mail: leim@mail.buct.edu.cn
Prof. Dr. J. L. Xiao
Department of Chemistry, University of Liverpool, Liverpool, L69
7ZD, UK
E-mail: j.xiao@liverpool.ac.uk
#These authors contributed equally. Supporting information for this
article is given via a link at the end of the document.((Please delete
this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/anie.201905870
Angewandte Chemie International Edition
RESEARCH ARTICLE
new chiral center generated.[11] In 2013, Oe and co-workers
reported the first asymmetric alkylation of achiral amines with
racemic alcohols with a chiral Ru catalyst, affording moderate
ees (<70%).[12] A major breakthrough was made by Zhao and
co-workers in 2014, who showed that chiral amines of up to
>99% ee can be formed by reacting achiral amines with racemic
alcohols using a chiral Ir catalyst in conjunction with a chiral
phosphoric acid (Figure 1).[13] This metal-Bronsted acid dual-
catalyt system has subsequently been exploited in various
asymmetric N-alkylation reactions.[14] In a further development,
Dong, Guan and their co-worker reported that racemic alcohols
can be aminated highly diastereoselectively with Ellman’s chiral
sulfinamide, using an achiral ruthenium catalyst with no need for
additional chiral additives (Figure 1).[15]
Mechanistically, the “borrowing hydrogen” strategy generally
involves dehydrogenation of the alcohol by a metal catalyst to
give a ketone and a metal hydride. This is followed by
enantioselective/diastereoselective reduction of the resulting
imine with the hydride. Circumventing the need for imines and
reductants and with water as the only by product, the method
has since been exploited for the synthesis of a range of chiral
amines by the groups of Beller,[16] Zhou,[17] and Popowycz[18]
(Figure 1). Whilst featuring high stereoselectivity, the borrowing-
hydrogen strategies reported so far necessitate the use of
transition metal catalysts, special chiral ligands or additives,
which could hamper its practical application in large-scale
pharmaceutical manufacturing.
reactions reported by Xu[22], Kang[22b] and coworkers, in which a
catalytic amount of an aldehyde initiates the reaction with the
catalysis sustained by aldehyde subsequently generated (vide
infra).
Somewhat intriguingly, the reaction rate was found to be
strongly affected by the choice of base, and in particular by the
cation of the inorganic base, with Na+ being most promoting
(Table S1, entries 8-11. Also see Table S5 for more details).
Using NaOH of 99.99% purity (Sigma-Aldrich), which contains
very low amounts of Ru, Rh, Ir, Pd and Fe (all <1 mg/kg) and Ni
(<5 mg/kg) as measured by ICP-MS analysis, in conjunction with
a new reaction tube and stir bar, the alkylation proceeded
equally well (Table S1, entry 12), suggesting that the reaction is
not catalyzed by trace transition metals and may not involve the
borrowing hydrogen process aforementioned. Instead, the base
may act as a catalyst for the transformation. Alkali metal cations
catalyzed-transfer hydrogenation and related reactions have
been reported previously; however, the role of the metal ions
has been rarely studied mechanistically.[23] Solvents appear also
important, with the apolar, non-protic toluene affording the
highest conversion (See Table S7 in SI for details). We also
noticed that the reaction is sensitive to air and water (See Table
S9 in SI for details). Thus, the substrates and solvents need to
be dried for small scale reactions and a Dean-Stark apparatus is
required for large scale ones (vide infra).
2. Scope of the amination. The substrate scope of this
transition metal-free system was then examined with various
alcohols with their corresponding ketones as the initial “catalyst”
(15 mol%). As is shown in Figure 2, under the conditions
established, the sulfinamide 3a was obtained in 72% isolated
yield and 99:1 dr as measured with HPLC. Both electron-
withdrawing and -donating substituents at the para position on
the phenyl ring of 1-phenylethanol were tolerated (Figure 2, 3b-
3j). Worth noting are the thioethers 2i and 3i, which could exert
a poisoning effect if a metal catalyst were used. However,
substrates bearing very electron-withdrawing substituents were
less active, as exemplified by the para-CF3-subsititued 2e, its
product 3e being obtained in a lower yield, and by the para-CN
or NO2-subsititued 1-phenylethanols, which were essentially
inactive in the reaction. This reduced activity stems probably
from their poor ability in participating in hydride transfer (vide
infra). 1-Phenylethanols bearing meta-substituents reacted
equally well, with the sulfinamides isolated in 64-84% yield and
>97:3 dr (3k-3q). Note that the yield of 3n is considerably higher
than that of 3e; the latter bears a more electron-withdrawing CF3
moiety (p 0.54 vs m 0.43). Moderate yields were obtained for
the electron-rich as well as electron-deficient disubstituted 1-
phenylethanols (3r vs 3s), with good diastereoselectivities
observed in all cases. The varied yields obtained are probably a
reflection of the intertwining electronic effect of the substituents
concerned at the meta vs para-positions of the phenyl ring.
However, 1-phenylethanols with ortho substitution and 1-
Herein, we present a transition metal-free asymmetric
alkylation of amines with racemic alcohols for the preparation of
α-chiral amines (Figure 1).[19] Under the co-catalysis of a ketone
and NaOH, racemic secondary alcohols reacted with Ellman’s
chiral sulfinamide,[20] affording α-chiral amines with high
diastereoselectivities (up to > 99:1 dr), which can be readily
converted into chiral primary amines following simple acidolysis.
Results and Discussion
1. Identification of
a metal-free asymmetric amination
protocol. In continuing our study of metal-catalyzed borrowing
hydrogen reactions,[21] we thought that it would be interesting to
replace the Ru complex of Dong, Guan and coworkers[15] with
cheaper Fe-based catalysts. Additional benefit would derive
from the use of Ellman’s sulfinamide, which allows for easy
access to chiral primary amines with wide industrial and
academic applications.[3] During the study, we serendipitously
found that in the presence of
acetophenone and a base, racemic 2-phenylethanol 2a was
aminated with (R)-(+)-tert-butanesulfinamide in toluene,
a catalytic amount of
1
affording the chiral amine product 3a with surprisingly good
diastereoselectivity (Eq. 1, and Table S1 in SI). For example, 3a
was obtained with 70% NMR yield and >95:5 dr in the presence
of acetophenone (40 mol%) and NaOH (50 mol%) (Table S1,
entry 1). Screening of the reaction conditions revealed that both
the ketone and base are essential (Table S1, entries 2-4);
however, the amount of ketone could be decreased to 15 mol%
without affecting the yield and selectivity of the reaction (Table
S1, entries 5-7). This ketone-catalyzed amination appears to be
reminiscent of the aldehyde-catalyzed achiral alkylation
This article is protected by copyright. All rights reserved.

10.1002/anie.201905870
Angewandte Chemie International Edition
RESEARCH ARTICLE
Figure 3. Scope of chiral deuterated amines. Reaction conditions: 1 (0.25
mmol), 4 (0.75 mmol), NaOH (50 mol%), and ketone (15 mol%) in solvent (2
mL) under N2 at 120 oC for 12 h, isolated yield. Deuterium ratios were
determined by 1H NMR analysis, and drs were determined by HPLC analysis.
important pharmaceutical applications, but are difficult to
prepare.[26] Thus, we exploited the amination in question for the
preparation of deuterium-labelled chiral amines. As shown in
Figure 3, highly deuterated sulfinamides alongside excellent
diastereoselectivities were achieved for the substrates examined
(Figure 3, 5a-5j). Since the racemic, deuterium-labelled alcohols
can be readily prepared via reduction of the corresponding
ketones with NaBD4, this protocol provides an operationally-
simple, transition metal-free route for the synthesis of chiral
deuterium-labelled amines, which should be of particular appeal
to pharmaceutical synthesis. Note that a significantly longer
reaction time is required for the amination of these alcohols
(Figures 2 vs 3), indicating that the turnover limiting step of the
amination may involve cleavage of the α-C-H bond of the alcohol.
The practical utility of the method was further examined in
larger scale reactions (Figure 4). Using a Dean-Stark apparatus
to remove the by-product water, the amination could be scaled
up to 10-gram scale, in the presence of only 25 mol% of NaOH
at 135 oC bath temperature. Under this condition, 3f was
obtained with 68% isolated yield and 98:2 dr. The dr of 3f could
be improved to >99:1 by column chromatography. To showcase
the easy access to chiral free primary amines with the protocol,
the so-isolated 3f was treated with hydrochloric acid, affording
the amine 6 with >99:1 er (Figure 4).
A better procedure was later found, which is simpler and
gives better yield to the free amine. During the amination, we
observed that the yield of the sulfinamide product would
decrease after prolonging the reaction time, as illustrated with
the amination of 2t with 1 (Figure 4, Eq. 2; also see Table S9 in
the SI). Careful examination of the resulting products revealed
that the amine product 3t decomposed into 3t’ under the
reaction conditions (cf Figure 2); but the total isolated yield of the
products was high, reaching 88%. This result prompted us to
propose a one-pot alkylation/hydrolysis process to access the
free amines. Delightfully, when the amination of 2f was carried
out this manner, the free amine 6 was obtained in 77% yield and
98:2 er (Figure 4, Eq. 3).
Figure 2. Scope of substrates. Unless otherwise noted, see entry 6 of Table
S1 for reaction conditions. Yields of 3 were isolated yield after silica gel
chromatography, and dr of 3 was determined by HPLC analysis. [a] (S)-(-)-tert-
butanesulfinamide 1a was used.
phenylpropan-1-ol showed only negligible activity, indicating that
steric effect dominates the amination of such alcohols, which is
similar to the metal-catalyzed reaction reported by Dong, Guan
and co-workers.[15]
Other aryl alcohols were also examined. 1-(Naphthalen-2-yl)
ethanol is a viable substrate for the reaction (3t). Cyclic alcohols,
such as 1-tetralol and 1-indanol also reacted, albeit with lower
yield and dr for 1-indanol (3u vs 3v). Whilst a low yield was
observed for the oxygen-containing heterocyclic alcohol (3w),
the thiophene alcohols afforded a high yield and dr (3x and 3y).
The chiral amine 3z with a pyridine ring was obtained with good
yield (74%) and dr (98 : 2) at a large scale of 5 mmol, which is a
high-value synthetic intermediate (> ¥2000 rmb/g for the free
amine)[24] (see SI for detailed conditions). Pleasingly, the
ferrocene moiety is tolerated, with 3aa obtained in 68% yield and
99:1 dr, which could be used for the synthesis of chiral
ligands.[25] To access the configurationally-opposite amine
products, all that is required is to replace the (R)-(+)-tert-
butanesulfinamide with its (S)-analogue, as exemplified by 3ac
and 3ad. A shortfall of the protocol is that it does not appear to
be suitable for aliphatic alcohols, as indicated by the poor yield
and diastereoselectivity obtained for octan-2-ol (3ab), possibly
due to the much-reduced differentiation between the two alkyl
groups. The metal-catalyzed amination mentioned above afford
better yields[15] and selectivity,[13] however.
During our mechanistic studies (vide infra), it was found that
the deuterium atom at the α-position of 1-phenylethanol remains
in the chiral amine product. Chiral deuterated amines have
This article is protected by copyright. All rights reserved.

10.1002/anie.201905870
Angewandte Chemie International Edition
RESEARCH ARTICLE
developed protocol as the key step (Figure 5).[29] The coupling of
4h (96% deuterium labelled) with 1 led to the expected chiral
amine 5h in 66% yield with >99:1 dr and full deuterium retention
after column chromatography purification. Subsequent removal
of the tert-butylsulfinyl group afforded (R)-7 in 74% yield, which
was reacted with 8 to yield the corresponding amide 9 in 88%
yield with > 99:1 er. Finally, compound 9 was reduced to afford
NPS R-568 10 in 69% isolated yield with >99:1 er and 95%
deuterium incorporation.
Starting with (S)-(+)-tert-butanesulfinamide 1a, the (S)-
enantiomer 12 was obtained via the same procedure as that for
7. N-Methylation of 12 afforded 13 in 84% yield with >99:1 er
and 95% deuterium incorporation. Cleavage of the O-methyl
group followed by ester formation gave the deuterated (S)-
rivastigmine 16 in 80% yield with 99:1 er and 94% deuterium
incorporation (Figure 5).
3. Experimental probing of the reaction mechanism.
While the scope of the protocol was studied, the mechanism of
the asymmetric amination was also considered. The high
deuterium ratios observed in the amine products presented
above are supportive of the assertion that the amination in
question does not involve transition metal catalysis, which would
promote easy H/D exchange. As both the ketone and the base
are indispensable for the reaction, we thought that the reaction
might proceed via a mechanism similar to that proposed for the
aldehyde-catalyzed achiral amination of alcohols mentioned
above.[22] Thus, taking the amination of 2-phenylethanol 2a with
(R)-(+)-tert-butanesulfinamide 1 as an example, the initially-
introduced catalytic ketone would react reversibly with 1 to form
an imine R-17, the reduction of which by the sodium salt of the
racemic 2a would then afford the diaseteromerically pure 3a
while releasing one new ketone molecule and the base used in
forming the alkoxide from 2a (Figure 6). The resulting ketone
would start a new cycle of amination, thus ensuring that only
catalytic ketone is necessary to initiate the reaction. This can be
viewed as a hydrogen autotransfer process,[22d] but involving no
hydrogen borrowing.
Figure 4. Gram scale reaction and one-pot alkylation/hydrolysis process. See
SI for experimental details.
Figure 6. Proposed mechanism for the ketone-catalyzed N-alkylation.
Figure 5. Stereoselective synthesis of deuterated NPS R-568 and deuterated
(S)-Rivastigmine.
A highly interesting question is how the hydrogen is
transferred between the alcohol and the imine and hence how
the diastereoselectivity of the reaction is determined.
Considering the well-known MPV mechanism for carbonyl
reduction with alcohols[30] and the proposed mechanisms for
nucleophilic addition to sulfinimines,[1b, 20e] the hydrogen transfer
in question may occur via a transition state as depicted in Figure
The practical utility of the method is also highlighted by the
synthesis of deuterium-labelled drug molecules. Taking
advantage of the easy availability of both enantiomers of
Ellman’s sulfinamide, the deuterium-labelled NPS R-568 (10) for
treating hyperparathyroidism[27] and (S)-Rivastigmine (16) for
treating Alzheimer’s disease[28] were synthesized, with this newly
This article is protected by copyright. All rights reserved.

10.1002/anie.201905870
Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 1. The effect of the configuration of alcohol and amine substrates on the
selectivity of the amination.
6, involving the Lewis acidic sodium cation bridging the alkoxide
and sulfinimine while the hydrogen of the former being
transferred. However, few mechanistic studies of such transition
metal-free reactions have been reported and in particular, little is
known of the mechanism of the hydrogen transfer step therein.[22,
31]
Subsequently, we carried out a series of experiments and
DFT calculations, in the hope to gain insight into the mechanism
of the asymmetric amination. Toward this end, the imine R-17
was first synthesized. Under the conditions established but in a
short reaction time of 1 h, R-17 was indeed reduced by 2a,
affording the amine 3a in 64% yield, thus supporting the
intermediary of an imine in the amination (Eq. S1 in Section 8 of
SI). Replacing 2a with the deuterium-labelled 4a resulted in a
significantly lower yield of 5a. This is suggestive of the turnover
rate of the amination being limited by the step of hydrogen
transfer, which involves C-H cleavage. A kinetic isotope effect is
indeed seen in the overall amination reaction (Figures 2 vs 3,
and Eq. S2 in Section 8 of SI), although it is less pronounced as
indicated in Eq. S1.[32]
If the reduction proceeds via the MPV type mechanism, the
cation of the base would be expected to influence the reaction
rate and/or selectivity. Indeed, Table S1 shows (Table S1,
entries 6 and 8-11) that sodium is the best cation for the reaction
under comparable conditions. The effect of the sodium cation on
the reaction is further seen in the amination when a crown ether
is present. Thus, as shown in Figure S1, with the introduction of
increasing amount of the crown ether 15-crown-5, which has a
high affinity for Na+,[33] the amination of 2a with 1 slowed down
progressively. This indicates strongly that the sodium cation is
involved in the rate-limiting step of the overall reaction,
presumably in an MPV transition state as shown in Figure 6.
Further insight into the diastereoselectivity-determining step
of hydrogen transfer was gained by examining the effect of the
configuration of the alcohol on the amination. As shown in Table
1, reacting the racemic 2a with an equal amount of R-1 and S-1,
respectively, afforded a similar yield of amine, but with opposite
configuration (Table 1, entries 1 and 2). Note that the er of the
unreacted 2a was approximately equal, indicating that 1 does
not preferentially aminate one of the enantiomers of 2a, leading,
consequently, to no kinetic resolution of the alcohol. More
interestingly, the same product (R,R)-3a was obtained when
either R-2a or S-2a was reacted with R-1 (Table 1, entries 3 and
4). Similar observations were made when the enantiomerically
pure alcohols were aminated with S-1 (Table 1, entries 5 and 6).
The most significant conclusion that could be drawn from the
above results is that the configuration of the amine product is
determined by the configuration of the sulfinamide 1, regardless
of that of the alcohol. A possible explanation is that both R-2a
and S-2a could react with the imine intermediate generated from
either R-1 or S-1, with only slight difference in rates. This
proposition finds support in DFT calculations (vide infra).
Entry[a]
Config. of
Config. of 1
er of unreacted 2a
(R:S)[b]
Config.
of
2a
3a’[c]
1
2
3
4
5
6
rac
rac
R
R
S
R
R
S
S
53:47
54:46
97:3
7:93
95:5
7:93
R,R
S,S
R,R
R,R
S,S
S,S
S
R
S
[a] Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), base (50 mol%), and
ketone (15 mol%), toluene (2 mL), under N2 at 120 oC for 6 h. [b] Determined
by HPLC analysis. [c] Absolute configuration determined by comparison with
literature.
isomer of 17 is 3.5 kcal/mol higher than the trans isomer. It is
obvious that the trans isomer is more stable, which is consistent
with the experimental results that only the trans imine was
observed for the isolated imine R-17. For this reason, our
discussion is focused on reactions of this imine.
Figure 7 shows the free energy profile of the hydrogenation
of the imine trans R-17 (denoted as R-17) with the sodium
alkoxide formed from 2a to give the amido adduct 19, hydrolysis
of which affords the chiral amine. The hydrogenation is
exergonic, as may be expected. There are four possible
pathways when R-17 interacts with the alkoxide, considering
that the alkoxide exists in the form of R- and S-alkoxide, each of
which can approach the imine on its re or si face. As can be
seen, when the S-alkoxide reacts with R-17 on its si face
(denoted as the R-S-si route), an intermediate adduct R-S-si-18
is formed exergonically, in which the Na ion is coordinated by
both the O and N atoms of the imine. Similarly, the reaction of
the R-alkoxide yields R-R-si-18. The reactions on the re face
give rise to R-S-re-18 and R-R-re-18. With the Na interacting
only with the nitrogen atom, these two adducts are less stable by
7.6 and 7.2 kcal/mol than R-S-si-18 and R-R-si-18, respectively.
On going from 18 to the amide 19, the hydridic hydrogen of the
alkoxide is transferred to the carbon atom of the imine moiety via
the transition state TS18-19. The free energy barrier of the
hydride transfer step is lower along the R-R-si and R-S-si
pathways, at 5.6 and 4.7 kcal/mol, respectively. In contrast, the
reactions along the R-R-re and R-S-re pathways are of
considerably higher barrier, at 9.6 and 9.4 kcal/mol, respectively,
and would lead to an amine with reversed configuration at the 
carbon. Thus, with either the R or S alkoxide, the hydrogen
addition occurs on the si face of the R-sulfinimine 17, affording
the same R,R-amido adduct 19.
4. Computational study of the hydride transfer step. To
probe the feasibility and the structure of a MPV type transition
state, DFT calculations were carried out on the step of hydrogen
transfer shown in Figure 6. Note that in addition to the R/S
configurational isomerism on the sulfoxide moiety, the imine
substrate 17 can exist as a trans and cis isomer, and
calculations showed that the absolute free energy of the cis
A closer look into the various possible species during the
hydride transfer is shown in Figure S2. We actually explored
twelve possible reaction pathways for the attack of the alkoxide
This article is protected by copyright. All rights reserved.

10.1002/anie.201905870
Angewandte Chemie International Edition
RESEARCH ARTICLE
Figure 7. Computed structures and free Gibbs energies of transition states and intermediates in the hydrogenation of imine R-17 with the sodium alkoxide formed
from 2a. All energies are denoted in kcal/mol, and interatomic distances are shown in angstroms.
at the R-17, including those of relatively low energies described
above (see Section 9 in SI for more details). Three reaction
modes were identified, which could lead to productive transition
states. Mode 1, displaying a [6+4] ring structure, corresponds to
the attack at R-17 along the R-R-si and R-S-si pathways, while
mode 2, featuring an eight-membered ring, is only found in the
R-S-si route involving no chelating interaction with the Na+.
attacking alkoxide, both of which are consistent with the
experimental observations (Table 1). By analogy, the imine S-17
will furnish the S,S-amine regardless of the attacking alkoxide
(See Figure S4 in SI). Clearly, it is the configuration of the
starting sulfonamide 1 that determines that of the amine product
in the amination under question, and this is made possible by
the Lewis acidic Na+ cation being able to bond with both the N
and O atoms of the sulfinimine moiety along the low-energy
pathway. It is also obvious that the hydride transfer step is the
chirality-determining step.
Similar observations concerning the cations of bases were
also made for base-catalyzed reduction of ketones via the MPV
mechanism.[23e] However, the reason for the cation effect
remains unclear. We thus further compared the transition states
of the rate-limiting hydride transfer step involving different
cations computationally. As shown in Figure S5 (See SI), on
replacing the Na atom with hydrogen in the structure of 18, the
free energy barrier of the hydride transfer from the S-alkoxide to
R-17 rises to 34.0 kcal/mol along the R-S-si pathway,
corroborating the experimental observation that without using a
base, the amination is infeasible under the conditions employed.
The instability of the transition state must at least partly stem
Similarly, mode 3, with
a six-membered ring structure,
corresponds to the R-R-re and R-S-re pathways for R-17 and
features no chelating interaction with the Na+. The figure shows
that only when both the Na6-N4 and Na6-O5 distances fall within a
bonding distance can the energy barrier of the hydride transfer
be lowered considerably. Furthermore, the C2 atom in mode 1
carries more positive charge compared with that in mode 2 and
3 (See Figure S3 in SI), which should facilitate the hydride
transfer.
Important insight into the key step of the amination can be
gleaned from the calculations. Thus, the differences in relative
energy by over 11 kcal/mol between the four transition states of
hydride transfer (Figure 7) suggest that for the imine R-17,
hydride transfer occurs on its si face to afford a R,R-product,
and this is the case regardless of the configuration of the
This article is protected by copyright. All rights reserved.

10.1002/anie.201905870
Angewandte Chemie International Edition
RESEARCH ARTICLE
Magid, S. J. Mehrman, Org. Proc. Res. Dev. 2006, 10, 971-1031; k) D.
Morton, R. A. Stockman, Tetrahedron 2006, 62, 8869-8905; l) P. V.
Ramachandran, T. E. Burghardt, Pure Appl. Chem. 2006, 78, 1397-
1406; m) G. K. Friestad, A. K. Mathies, Tetrahedron 2007, 63, 2541-
2569; n) J.-C. Kizirian, Chem. Rev. 2007, 108, 140-205; o) A. J.
Minnaard, B. L. Feringa, L. Lefort, J. G. de Vries, Acc. Chem. Res.
2007, 40, 1267-1277; p) M. Petrini, E. Torregiani, Synthesis 2007, 2007,
159-186; q) E. Skucas, M.-Y. Ngai, V. Komanduri, M. J. Krische, Acc.
Chem. Res. 2007, 40, 1394-1401; r) S.-L. You, Chem. Asian J. 2007, 2,
820-827; s) H. U. Blaser, S. Felix, Enatioselective Hydrogenation of
from the hydrogen being unable to interact with the nitrogen of
R-17. Similarly, replacing the Na with a Li atom in 18 also raises
the energy barrier, albeit much less significantly, to 7.4 kcal/mol.
This is again in line with the observation that a sodium-
containing base gives faster amination. Note that whilst like Na,
Li bonds with both the nitrogen and oxygen atoms, the C2 atom
in R-S-si-TS18-19-Na carries more positive charge than in R-S-
si-TS18-19-Li, and in the case of R-S-si-TS18-19-H, the C2 atom
is even slightly negatively charged, suggesting the C=N bond in
R-S-si-TS18-19-Na to be most electrophilic and thus more
reactive toward the hydride donor. Cation bonding with the O or
N atoms or both has often been invoked in the transition state of
nucleophilic addition to sulfinimines.[34] However, it appears to us
that there has been no reported study of whether or how the
cation may affect the reaction thus far.
̈
C=N Functions and Enamines, Wiley-VCH 2008; t) T. E. Muller, K. C.
Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem. Rev. 2008, 108, 3795-
3892; u) R. P. Tripathi, S. S. Verma, J. Pandey, V. K. Tiwari, Curr Org
Chem 2008, 12, 1093-1115; v) T. C. Nugent, M. El-Shazly, Adv. Synth.
Catal. 2010, 352, 753-819; w) C. Wang, B. Villa-Marcos, J. Xiao, Chem.
Commun. 2011, 47, 9773-9785; x) J.-H. Xie, S.-F. Zhu, Q.-L. Zhou,
Chem. Soc. Rev. 2012, 41, 4126-4139.
[2]
a) H.-U. Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer,
Adv. Synth. Catal. 2003, 345, 103-151; b) N. Fleury-Brégeot, V. de la
Fuente, S. Castillón, C. Claver, Chemcatchem 2010, 2, 1346-1371; c)
J.-H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011, 111, 1713-1760; d)
W. Li, X. Zhang, in Stereoselective Formation of Amines (Eds.: W. Li, X.
Zhang), Springer Berlin Heidelberg, Berlin, Heidelberg, 2014, pp. 103-
144; e) C. Wang, J. Xiao, in Stereoselective Formation of Amines (Eds.:
W. Li, X. Zhang), Springer Berlin Heidelberg, Berlin, Heidelberg, 2014,
pp. 261-282.
Conclusion
We have developed a practical, convenient, and transition-
metal-free method for the synthesis of α-chiral amines via
alkylation of amines with alcohols. Using cheap, readily available
racemic alcohols and Ellman’s chiral sulfinamide, this highly
diastereoselective protocol is easy to operate and scale-up,
while avoiding transition-metal contamination, thus providing an
attractive route for the synthesis of α-chiral primary amines for
the pharmaceutical industry. Chiral deuterium-labelled amines,
including chiral deuterated drugs, could be readily synthesized
with high deuterium incorporation and optical purity. Mechanistic
studies including DFT calculations showed that this hydrogen
autotransfer reaction is initiated by a ketone catalyst and the
cation of the base plays a critical role in the hydride transfer step,
bonding with both the nitrogen and oxygen atoms of the
intermediate sulfinimine in the transition state. Of further interest
is the finding that the configuration of amine products is
determined solely by the configuration of the chiral tert-
butanesulfinamide regardless of that of the alcohols, which is
rationalized by DFT calculations.
[3]
a) R. Kadyrov, T. H. Riermeier, Angew. Chem. Int. Ed. 2003, 42, 5472-
5474; b) G. Hou, F. Gosselin, W. Li, J. C. McWilliams, Y. Sun, M.
Weisel, P. D. O’Shea, C.-Y. Chen, I. W. Davies, X. Zhang, J. Am.
Chem. Soc. 2009, 131, 9882-9883; c) D. Steinhuebel, Y. Sun, K.
Matsumura, N. Sayo, T. Saito, J. Am. Chem. Soc. 2009, 131, 11316-
11317; d) G. Hou, W. Li, M. Ma, X. Zhang, X. Zhang, J. Am. Chem. Soc.
2010, 132, 12844-12846; e) G. Hou, R. Tao, Y. Sun, X. Zhang, F.
Gosselin, J. Am. Chem. Soc. 2010, 132, 2124-2125; f) Q. Zhao, J. Wen,
R. Tan, K. Huang, P. Metola, R. Wang, E. V. Anslyn, X. Zhang, Angew.
Chem. Int. Ed. 2014, 53, 8467-8470; g) J. Gallardo-Donaire, M.
Hermsen, J. Wysocki, M. Ernst, F. Rominger, O. Trapp, A. S. K.
Hashmi, A. Schäfer, P. Comba, T. Schaub, J. Am. Chem. Soc. 2018,
140, 355-361; h) X. Tan, S. Gao, W. Zeng, S. Xin, Q. Yin, X. Zhang, J.
Am. Chem. Soc. 2018, 140, 2024-2027.
[4]
[5]
a) T. Vries, H. Wynberg, E. van Echten, J. Koek, W. ten Hoeve, R. M.
Kellogg, Q. B. Broxterman, A. Minnaard, B. Kaptein, S. van der Sluis, L.
Hulshof, J. Kooistra, Angew. Chem. Int. Ed. 1998, 37, 2349-2354; b) M.
Breuer, K. Ditrich, T. Habicher, B. Hauer, M. Keßeler, R. Stürmer, T.
Zelinski, Angew. Chem. Int. Ed. 2004, 43, 788-824.
Acknowledgements
This research was supported by the National Natural Science
Foundation of China (21773145, 21672018, 2161101308),
Projects for the Academic Leaders and Academic Backbones,
Shaanxi Normal University (16QNGG008), the 111 project
(B14041), and the Fundamental Research Funds for the Central
Universities (GK201803079). We also thank the Royal Society
(UK) for a Newton Mobility Grant.
a) S. M. A. De Wildeman, T. Sonke, H. E. Schoemaker, O. May, Acc.
Chem. Res. 2007, 40, 1260-1266; b) M. Höhne, U. T. Bornscheuer,
Chemcatchem 2009, 1, 42-51; c) C. K. Savile, J. M. Janey, E. C.
Mundorff, J. C. Moore, S. Tam, W. R. Jarvis, J. C. Colbeck, A. Krebber,
F. J. Fleitz, J. Brands, P. N. Devine, G. W. Huisman, G. J. Hughes,
Science 2010, 329, 305-309; d) A. A. Desai, Angew. Chem. Int. Ed.
2011, 50, 1974-1976; e) M. Hall, A. S. Bommarius, Chem. Rev. 2011,
111, 4088-4110; f) F. Hollmann, I. W. C. E. Arends, D. Holtmann,
Green Chem. 2011, 13, 2285-2314; g) E. Ricca, B. Brucher, J. H.
Schrittwieser, Adv. Synth. Catal. 2011, 353, 2239-2262; h) F. Guo, P.
Berglund, Green Chem. 2017, 19, 333-360; i) I. Slabu, J. L. Galman, R.
C. Lloyd, N. J. Turner, ACS Catal. 2017, 7, 8263-8284; j) S. A. Kelly, S.
Pohle, S. Wharry, S. Mix, C. C. R. Allen, T. S. Moody, B. F. Gilmore,
Chem. Rev. 2018, 118, 349-367; k) J. H. Schrittwieser, S. Velikogne, M.
Hall, W. Kroutil, Chem. Rev. 2018, 118, 270-348.
Keywords: chiral amine • alcohol • tert-butanesulfinamide •
alkylation • deuterium drug
[1]
a) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069-1094; b) J. A.
Ellman, T. D. Owens, T. P. Tang, Acc. Chem. Res. 2002, 35, 984-995;
c) S. Gomez, J. A. Peters, T. Maschmeyer, Adv. Synth. Catal. 2002,
344, 1037-1057; d) M. Besson, C. Pinel, Top. Catal. 2003, 25, 43-61; e)
H.-U. Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer,
Adv. Synth. Catal. 2003, 345, 103-151; f) J. A. Ellman, Pure Appl.
Chem. 2003, 75, 39-46; g) P. Kukula, R. Prins, Top. Catal. 2003, 25,
29-42; h) G. K. Friestad, Eur. J. Org. Chem. 2005, 2005, 3157-3172; i)
V. I. Tararov, A. Börner, Synlett 2005, 2005, 203-211; j) A. F. Abdel-
[6]
a) W. Tang, X. Zhang, Chem. Rev. 2003, 103, 3029-3070; b) A.
Fabrello, A. Bachelier, M. Urrutigoïty, P. Kalck, Coord. Chem. Rev.
2010, 254, 273-287; c) A. Bartoszewicz, N. Ahlsten, B. Martín-Matute,
Chem. Eur. J. 2013, 19, 7274-7302; d) Q.-A. Chen, Z.-S. Ye, Y. Duan,
Y.-G. Zhou, Chem. Soc. Rev. 2013, 42, 497-511; e) P. Etayo, A. Vidal-
Ferran, Chem. Soc. Rev. 2013, 42, 728-754; f) K. H. Hopmann, A.
This article is protected by copyright. All rights reserved.

10.1002/anie.201905870
Angewandte Chemie International Edition
RESEARCH ARTICLE
Bayer, Coord. Chem. Rev. 2014, 268, 59-82; g) D. Dario, G. A.
Carmela, Curr. Org. Chem. 2016, 20, 2552-2590; h) P.-G. Echeverria,
T. Ayad, P. Phansavath, V. Ratovelomanana-Vidal, Synthesis 2016, 48,
2523-2539; i) Asymmetric Catalysis on Industrial Scale: Challenges,
Approaches and Solutions (Eds.: H. U. Blaser, H. J. Federsel), 2nd ed.,
Wiley-VCH, Weinheim, 2010.
[22] a) Q. Xu, Q. Li, X. Zhu, J. Chen, Adv. Synth. Catal. 2013, 355, 73-80; b)
Q.-Q. Li, Z.-F. Xiao, C.-Z. Yao, H.-X. Zheng, Y.-B. Kang, Org. Lett.
2015, 17, 5328-5331; c) X. Li, S. Li, Q. Li, X. Dong, Y. Li, X. Yu, Q. Xu,
Tetrahedron 2016, 72, 264-272; d) X. Ma, C. Su, Q. Xu, Top. Curr.
Chem. 2016, 374, 27.
[23] a) W. v. E. Doering, T. C. Aschner, J. Am. Chem. Soc. 1953, 75, 393-
397; b) R. L. Chowdhury, J. E. Backvall, J. Chem. Soc. Chem.
Commun. 1991, 1063-1064; c) J. R. Miecznikowski, R. H. Crabtree,
Organometallics 2004, 23, 629-631; d) J. Ekström, J. Wettergren, H.
Adolfsson, Adv. Synth. Catal. 2007, 349, 1609-1613; e) A. Ouali, J.-P.
Majoral, A.-M. Caminade, M. Taillefer, ChemCatChem 2009, 1, 504-
509; f) V. Polshettiwar, R. S. Varma, Green Chem. 2009, 11, 1313-
1316; g) L. J. Allen, R. H. Crabtree, Green Chem. 2010, 12, 1362-1364;
h) R. Radhakrishan, D. M. Do, S. Jaenicke, Y. Sasson, G.-K. Chuah,
ACS Catal. 2011, 1, 1631-1636; i) Y.-F. Liang, X.-F. Zhou, S.-Y. Tang,
Y.-B. Huang, Y.-S. Feng, H.-J. Xu, RSC Adv. 2013, 3, 7739-7742; j) J.
Ballester, A.-M. Caminade, J.-P. Majoral, M. Taillefer, A. Ouali, Catal.
Commun. 2014, 47, 58-62; k) D. Wang, C. Deraedt, J. Ruiz, D. Astruc,
J. Mol. Catal. A: Chem. 2015, 400, 14-21; l) H. Bauer, M. Alonso, C.
Färber, H. Elsen, J. Pahl, A. Causero, G. Ballmann, F. De Proft, S.
Harder, Nat. Catal. 2018, 1, 40-47; m) M. Xu, A. R. Jupp, Z.-W. Qu, D.
W. Stephan, Angew. Chem. Int. Ed. 2018, 57, 11050-11054; n) D. C.
Elliott, A. Marti, P. Mauleón, A. Pfaltz, Chem. Eur. J. 2019, 25, 1918-
1922.
[7]
[8]
H. U. Blaser, H. P. Buser, K. Loers, R. Hanreich, H. P. Jalett, E. Jelsch,
B. Pugin, H. D. Schneider, F. Spindler, A. Wagmann, Chimia 1999, 53,
275-280.
a) M. H. S. A. Hamid, P. A. Slatford, J. M. J. Williams, Adv. Synth. Catal.
2007, 349, 1555-1575; b) G. Guillena, D. J. Ramón, M. Yus, Chem.
Rev. 2009, 110, 1611-1641; c) T. D. Nixon, M. K. Whittlesey, J. M. J.
Williams, Dalton Trans. 2009, 753-762; d) G. E. Dobereiner, R. H.
Crabtree, Chem. Rev. 2010, 110, 681-703; e) A. J. A. Watson, J. M. J.
Williams, Science 2010, 329, 635-636; f) J. Choi, A. H. R. MacArthur, M.
Brookhart, A. S. Goldman, Chem. Rev. 2011, 111, 1761-1779; g) A. C.
Marr, Catal. Sci. Technol. 2012, 2, 279-287; h) C. Gunanathan, D.
Milstein, Science 2013, 341, 1229712; i) S. Pan, T. Shibata, ACS Catal.
2013, 3, 704-712; j) Y. Obora, ACS Catal. 2014, 4, 3972-3981; k) A.
Nandakumar, S. P. Midya, V. G. Landge, E. Balaraman, Angew. Chem.
Int. Ed. 2015, 54, 11022-11034; l) S. Werkmeister, J. Neumann, K.
Junge, M. Beller, Chem. Eur. J. 2015, 21, 12226-12250; m) Q. Yang, Q.
Wang, Z. Yu, Chem. Soc. Rev. 2015, 44, 2305-2329; n) Y. Nakamura,
A. E. Putra, Y. Oe, T. Ohta, J. Syn. Org. Chem. Jpn. 2016, 74, 1182-
1193; o) R. H. Crabtree, Chem. Rev. 2017, 117, 9228-9246; p) C.
Wang, J. Xiao, Chem. Commun. 2017, 53, 3399-3411.
[24] The price for the hydrochloride salt of 3z is 8536 rmb/g from J & K
Scientific.
[9]
K.-i. Fujita, T. Fujii, R. Yamaguchi, Org. Lett. 2004, 6, 3525-3528.
[25] a) T. J. Colacot, Chem. Rev. 2003, 103, 3101-3118; b) R. Gómez
Arrayás, J. Adrio, J. C. Carretero, Angew. Chem. Int. Ed. 2006, 45,
7674-7715.
[10] L. Miao, S. C. DiMaggio, H. Shu, M. L. Trudell, Org. Lett. 2009, 11,
1579-1582.
[11] M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C. Maxwell, H. C.
Maytum, A. J. A. Watson, J. M. J. Williams, J. Am. Chem. Soc. 2009,
131, 1766-1774.
[26] a) L. Neubert, D. Michalik, S. Bähn, S. Imm, H. Neumann, J. Atzrodt, V.
Derdau, W. Holla, M. Beller, J. Am. Chem. Soc. 2012, 134, 12239-
12244; b) T. Sakamoto, K. Mori, T. Akiyama, Org. Lett. 2012, 14, 3312-
3315; c) W. Bai, K.-H. Lee, S. K. S. Tse, K. W. Chan, Z. Lin, G. Jia,
Organometallics 2015, 34, 3686-3698; d) C. Taglang, L. M. Martínez-
Prieto, I. del Rosal, L. Maron, R. Poteau, K. Philippot, B. Chaudret, S.
Perato, A. Sam Lone, C. Puente, C. Dugave, B. Rousseau, G. Pieters,
Angew. Chem. Int. Ed. 2015, 54, 10474-10477; e) L. V. A. Hale, N. K.
Szymczak, J. Am. Chem. Soc. 2016, 138, 13489-13492; f) Y. Y. Loh, K.
Nagao, A. J. Hoover, D. Hesk, N. R. Rivera, S. L. Colletti, I. W. Davies,
D. W. C. MacMillan, Science 2017, 358, 1182-1187; g) W. N. Palmer, P.
J. Chirik, ACS Catal. 2017, 7, 5674-5678; h) M. Valero, R. Weck, S.
Güssregen, J. Atzrodt, V. Derdau, Angew. Chem. Int. Ed. 2018, 57,
8159-8163; i) H. Yang, P. G. Dormer, N. R. Rivera, A. J. Hoover,
Angew. Chem. Int. Ed. 2018, 57, 1883-1887.
[12] A. Eka Putra, Y. Oe, T. Ohta, Eur. J. Org. Chem. 2013, 2013, 6146-
6151.
[13] Y. Zhang, C.-S. Lim, D. S. B. Sim, H.-J. Pan, Y. Zhao, Angew. Chem.
Int. Ed. 2014, 53, 1399-1403.
[14] a) Z.-Q. Rong, Y. Zhang, R. H. B. Chua, H.-J. Pan, Y. Zhao, J. Am.
Chem. Soc. 2015, 137, 4944-4947; b) C. S. Lim, T. T. Quach, Y. Zhao,
Angew. Chem. Int. Ed. 2017, 56, 7176-7180; c) L.-C. Yang, Y.-N. Wang,
Y. Zhang, Y. Zhao, ACS Catal. 2017, 7, 93-97; d) S. Tribedi,
Christopher M. Hadad, R. B. Sunoj, Chem Sci. 2018, 9, 6126-6133.
[15] N. J. Oldenhuis, V. M. Dong, Z. Guan, J. Am. Chem. Soc. 2014, 136,
12548-12551.
[16] M. Peña-López, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 2016,
55, 7826-7830.
[27] R. Rao, M. P. Shewalkar, R. Nandipati, J. S. Yadav, M. Khagga, D. B.
Shinde, Synth. Commun. 2012, 42, 589-598.
[17] P. Yang, C. Zhang, Y. Ma, C. Zhang, A. Li, B. Tang, J. S. Zhou, Angew.
Chem. Int. Ed. 2017, 56, 14702-14706.
[28] a) C. M. Spencer, S. Noble, Drugs & Aging 1998, 13, 391-411; b) P.-C.
Yan, G.-L. Zhu, J.-H. Xie, X.-D. Zhang, Q.-L. Zhou, Y.-Q. Li, W.-H.
Shen, D.-Q. Che, Org. Proc. Res. Dev. 2013, 17, 307-312.
[29] a) V. N. Wakchaure, P. S. J. Kaib, M. Leutzsch, B. List, Angew. Chem.
Int. Ed. 2015, 54, 11852-11856; b) A. Chelouan, R. Recio, L. G.
Borrego, E. Álvarez, N. Khiar, I. Fernández, Org. Lett. 2016, 18, 3258-
3261.
[18] M. Jacolot, S. Moebs-Sanchez, F. Popowycz, J. Org. Chem. 2018, 83,
9456-9463.
[19] M. Chen, Y. Han, D. Ma, Y. Wang, Z. Lai, J. Sun, Chin. J. Chem. 2018,
36, 587-593. This is an elegant example of organocatalytic N-alkylation
with alcohols via SN1 mechanism.
[20] a) G. Liu, D. A. Cogan, J. A. Ellman, J. Am. Chem. Soc. 1997, 119,
9913-9914; b) D. A. Cogan, G. Liu, K. Kim, B. J. Backes, J. A. Ellman, J.
Am. Chem. Soc. 1998, 120, 8011-8019; c) D. J. Weix, J. A. Ellman, Org.
Lett. 2003, 5, 1317-1320; d) M. Wakayama, J. A. Ellman, J. Org. Chem.
2009, 74, 2646-2650; e) M. T. Robak, M. A. Herbage, J. A. Ellman,
Chem. Rev. 2010, 110, 3600-3740.
[30] a) C. F. de Graauw, J. A. Peters, H. van Bekkum, J. Huskens,
Synthesis 1994, 1994, 1007-1017; b) K. Nishide, M. Node, Chirality
2002, 14, 759-767; c) J. S. Cha, Org. Proc. Res. Dev. 2006, 10, 1032-
1053.
[31] Q. Xu, J. Chen, H. Tian, X. Yuan, S. Li, C. Zhou, J. Liu, Angew. Chem.
Int. Ed. 2014, 53, 225-229.
[21] a) Q. Zou, C. Wang, J. Smith, D. Xue, J. Xiao, Chem. Eur. J. 2015, 21,
9656-9661; b) J. Cheng, M. Zhu, C. Wang, J. Li, X. Jiang, Y. Wei, W.
Tang, D. Xue, J. Xiao, Chem Sci. 2016, 7, 4428-4434; c) X. Jiang, W.
Tang, D. Xue, J. Xiao, C. Wang, ACS Catal. 2017, 7, 1831-1835; d) J.
Li, Y. Liu, W. Tang, D. Xue, C. Li, J. Xiao, C. Wang, Chem. Eur. J. 2017,
23, 14445-14449; e) W. Ma, S. Cui, H. Sun, W. Tang, D. Xue, C. Li, J.
Fan, J. Xiao, C. Wang, Chem. Eur. J. 2018, 24, 13118-13123.
[32] This weakened effect may be due to a preequilibrium between the
ketone/amine and imine, preceding the turnover limiting reduction of the
imine by the alkoxide.
[33] T. Yasuyuki, K. Koji, I. Yoshihisa, H. Tadao, Bull. Chem. Soc. Jpn. 1988,
61, 627-632.
[34] T. P. Tang, J. A. Ellman, J. Org. Chem. 1999, 64, 12-13.
This article is protected by copyright. All rights reserved.

10.1002/anie.201905870
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
RESEARCH ARTICLE
M. Xiao, X. Yue, R. R. Xu, W. J. Tang,
D. Xue, C. Q. Li, M. Lei,* J. L. Xiao,* C.
Wang*
Page No. – Page No.
Transition-Metal-Free Hydrogen
Autotransfer: Diastereoselective N-
Alkylation of Amines with Racemic
Alcohols
An asymmetric hydrogen autotransfer reaction has been found, which allows for the
practical synthesis of α-chiral amines via alkylation of amines with alcohols. Under
the co-catalysis of a ketone and NaOH, racemic secondary alcohols reacted with
Ellman’s chiral tert-butanesulfinamide, affording chiral amines with high
diastereoselectivities (up to > 99:1 dr).
This article is protected by copyright. All rights reserved.