Anti-Markovnikov Hydroamination of Racemic Allylic Alcohols to Access Chiral γ-Amino Alcohols

Article abstract of DOI:10.1002/anie.202009754

A ruthenium-catalyzed formal anti-Markovnikov hydroamination of allylic alcohols for the synthesis of chiral γ-amino alcohols is presented. Proceeding via an asymmetric hydrogen-borrowing process, the catalysis allows racemic secondary allylic alcohols to react with various amines, affording enantiomerically enriched chiral γ-amino alcohols with broad substrate scope and excellent enantioselectivities (68 examples, up to >99 % ee).

Full text of DOI:10.1002/anie.202009754

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Anti-Markovnikov Hydroamination of Racemic Allylic Alcohols to
Access Chiral γ-Amino Alcohols
Authors: Ruirui Xu, Kun Wang, Haoying Liu, Weijun Tang, Huaming
Sun, Dong Xue, 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.202009754
Link to VoR: https://doi.org/10.1002/anie.202009754

10.1002/anie.202009754
Angewandte Chemie International Edition
COMMUNICATION
Anti-Markovnikov Hydroamination of Racemic Allylic Alcohols to
Access Chiral γ-Amino Alcohols
Ruirui Xu,+[a] Kun Wang,+[a] Haoying Liu,[a] Weijun Tang,[a] Huaming Sun,[a] Dong Xue,[a] Jianliang
Xiao[b] and Chao Wang*[a]
[a]
R. R. Xu, K. Wang, H. Y. Liu, Prof. Dr. W. J. Tang, Dr. H. M. Sun, Prof. Dr. D. Xue, 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]
[+]
Prof. Dr. J. L. Xiao
Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
ruthenium-catalyzed
formal
anti-Markovnikov
hydroamination of allylic alcohols for the synthesis of chiral γ-amino
alcohols is presented. Proceeding via an asymmetric hydrogen-
borrowing process, the catalysis allows racemic secondary allylic
alcohols to react with various amines, affording enantiomerically
enriched chiral γ-amino alcohols with broad substrate scope and
excellent enantioselectivities (68 examples, up to >99% ee).
Chiral γ-amino alcohols serve as key intermediates for the
synthesis of many drug and biologically active molecules.
Examples are seen in the drug molecules (S)-Duloxetine, (R)-
Atomoxetine and Fluoxetine (Figure 1a).[1] They can also be
employed as chiral auxiliaries and ligands for asymmetric
synthesis and catalysis.[2] A number of methods have been
developed for the synthesis of enantiomerically enriched chiral
γ-amino alcohols,[3] with asymmetric hydrogenation of β-amino
ketones[4] being one of the most favored choices. Asymmetric
hydroamination of allylic alcohols provides another ideal atom-
economic approach to access chiral γ-amino alcohols, as
pioneered by Buchwald and coworkers.[5] However, the
traditional hydroamination[6] of allylic alcohols could only produce
chiral γ-amino alcohols with the stereogenic center adjacent to
the nitrogen atom (Figure 1b).[5]
A different approach for asymmetric γ-functionalization of
allylic alcohols is via hydrogen-borrowing catalysis.[7] Quintard[8]
and Dydio[9] have elegantly demonstrated that primary allylic
alcohols could react with carbon nucleophiles via hydrogen-
borrowing to afford γ-chiral primary alcohols,[10] in which an
achiral hydrogen-borrowing catalyst is cascaded with a chiral C-
C coupling catalyst (Figure 1c). Oe[11] and more recently we[12]
have shown that the hydrogen-borrowing strategy could be
employed for the formal anti-Markovnikov hydroamination of
allylic alcohols to give racemic γ-amino alcohols. This finding
could offer a new pathway for chiral γ-amino alcohols, departing
from the common asymmetric hydroamination strategy.
Specifically, if a viable chiral hydrogen-borrowing catalyst can be
identified that enables the dehydrogenation of a racemic
secondary allylic alcohol as well as the subsequent asymmetric
hydrogenation of the resulting amino ketone intermediate, chiral
γ-amino alcohols with the stereogenic center adjacent to the OH
group could be obtained (Figure 1d). Herein, we report that a
chiral Ru-diamine-diphosphine complex catalyzes the formal
anti-Markovnikov hydroamination of racemic secondary allylic
alcohols to give enantiomerically enriched chiral γ-amino
Figure 1. Drugs containing chiral γ-amino alcohol units and methods for
asymmetric γ-functionalization of allylic alcohols.
alcohols with the stereogenic center adjacent to the OH
group.[13] Note that this kind of chiral γ-amino alcohols is
otherwise impossible to get via the normal asymmetric
hydroamination[5] (Figure 1b), and the selectivity pattern realized
is different from the previously reported γ-functionalization of
allylic alcohols[7-8] (Figure 1c).
We recently showed the feasibility of formal anti-
Markovnikov hydroamination of allylic alcohols with an achiral
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202009754
Angewandte Chemie International Edition
COMMUNICATION
iron catalyst via hydrogen borrowing.[12] Our further work using a
similar approach has revealed that the Guerbet reaction can be
made enantioselective with a chiral Ru-diamine-diphosphine
catalyst, in which an intermediary ketone is reduced to a chiral
alcohol product.[10q] We envisioned that such chiral Ru-diamine-
diphosphine catalysts could be utilized for the formal
hydroamination of racemic secondary allylic alcohols, which
would produce chiral γ-amino alcohols (Figure 1d). Thus, we
commenced our study by investigating the reaction between the
racemic 1-phenylprop-2-en-1-ol 1a with 1-phenylpiperazine 2a
using Ru-diamine-diphosphine catalysts. According to our
previous study,[12] 1.5 equivalent of 1a (relative to 2a) was used.
The initial results are indeed encouraging. With the Noyori
catalyst[14] 3a (1 mol%), which was used for the asymmetric
cross coupling of alcohols in our previous study,[10q] the desired
product 4a was obtained in 97% ee, albeit with a low yield of
10%, in the presence of 0.5 equivalent of K3PO4 in toluene at 30
oC for 12 h under Ar (Table 1, entry 1). Similar results were
obtained with another Noyori catalyst 3b[14] (Table 1, entry 2). A
sharp increase of activity was observed with catalyst 3c, which
was developed by Ohkuma[15] and commercialized by Takasago
(Table 1, entry 3). The diamine ligand is essential for the activity
observed, as demonstrated with complex 3d (Table 1, entry 4).
The yield could be improved to 94% by increasing the amount of
K3PO4 to 1.5 equivalents without adversely affecting the
enantioselectivity (Table 1, entry 5). Control experiments
showed that both the catalyst and the base were indispensable
for the transformation (Table 1, entries 6 and 7). The absolute
configuration of 4a was determined to be
S by X-ray
crystallography. The solid state structure indicates that there
exists a hydrogen bonding interaction between the OH moiety
and the γ-N atom (The O-HꞏꞏꞏN distance is 2.080 Å), which,
along with the enhanced steric bulkiness in the product, may
explain why the reverse dehydrogenation of the product appears
to be negligible, unlike the Guerbet reaction.[10q]
With optimal conditions in hand, the generality of the
method was evaluated (Figure 2). The reaction time was
prolonged to 48 h in most cases and 2 mol% of 3c was used in
some cases, to ensure maximum yields. Isolated yields were
obtained for all the products. The reaction of various racemic
allylic alcohols with 2a was first examined (Figure 2, 4a-4ab).
Both electron-donating and -withdrawing substituents on the
meta- and para-positions of the phenyl ring of allylic alcohols
could be well tolerated, the corresponding γ-amino alcohols
Table 1. Optimization of reaction conditions.
being
obtained
with
good
yields
and
excellent
enantioselectivities (4d-4p). However, low activities were
observed for ortho-substituted substrates (4b, 4c), suggesting
that the reaction is sensitive to steric hindrance. Allylic alcohols
with naphthyl, di-substituted phenyl, and heterocyclic groups are
all viable (4s-4y), albeit with low yield for 4u. A limitation of the
protocol is that the enantioselectivities for allylic alcohols with
benzyl or aliphatic groups adjacent to the alcohol carbon are
quite low (4z-4ab). X-ray structures were obtained for products
4j, 4n and 4o, confirming their absolute configuration to be S. As
with 4a, for almost all the X-ray structures determined, hydrogen
bonds between the OH group and its γ-nitrogen atom are
observed.
The substrate scope for amines were then investigated
with 1-(4-bromophenyl)prop-2-en-1-ol (Figure 2, 5a-5aj).
Excellent enantioselectivities were obtained for all the cyclic
secondary amines, including both six and five membered rings
(5a-5x). The structures of 5g and 5l were confirmed by X-ray
crystallography. Acyclic secondary amines could also be
employed as substrates (5y-5ah). However, low yields were
obtained for acyclic secondary aromatic amines (5af-5ah). The
low activities could be due to their low nucleophilicity and
relatively large steric hindrance. Almost no reaction took place
for primary aromatic amines, although moderate yield and good
ee were observed for an example of primary aliphatic amine
(5ai).
Entry[a]
Catalyst
Base (equiv.)
K3PO4 (0.5)
K3PO4 (0.5)
K3PO4 (0.5)
K3PO4 (0.5)
K3PO4 (1.5)
-
Yield (%)[b]
ee (%)[c]
1
2
3
4
5
6
7
3a
3b
3c
3d
3c
3c
-
10
20
85
0
97
98
98
-
94
0
98
-
K3PO4 (1.5)
0
-
As many natural products and drugs contain secondary
amine structures, this protocol could be used for the modification
of natural products and drugs. This is demonstrated by the
functionalization of Cytisine and Amoxapine, leading to 5aj and
5ak (Figure 2). The utility of the reaction is further demonstrated
by a gram-scale preparation of the key intermediate (6, X-ray
structure obtained) for the synthesis of a potential analgesic
agent[16] (Figure 3a), and intermediates for the synthesis of (S)-
Fluoxetine (7)[3q,3t] (Figure 3b), an antidepressant (sold in
racemate), and (S)-Duloxetine (8)[3q,3t] (Figure 3c), an
antidepressant and anxiolytic. Notably, the enantioselectivities
remained excellent for these relatively large-scale reactions.
[a] Reaction conditions: 1a (0.375 mmol), 2a (0.25 mmol), catalyst (1 mol%),
base, toluene (1 mL), 30 oC, under Ar, 12 h. [b] Determined by 1H NMR
analysis with 1,3,5-trimethoxybenzene as an internal standard. [c] The
enantiomeric excess (ee) was determined by HPLC analysis of pure isolated
product, and the absolute configuration of 4a was determined to be S by X-ray
crystallography.
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202009754
Angewandte Chemie International Edition
COMMUNICATION
Figure 2. Substrate scope for the formal asymmetric hydroamination of allylic alcohols. General reaction conditions: allylic alcohol (0.375 mmol), amine (0.25
mmol), K3PO4 (0.375 mmol), 3c (1-2 mol%), toluene (1 mL), 30 oC, under Ar, isolated yield. See SI for detailed conditions for each product.
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202009754
Angewandte Chemie International Edition
COMMUNICATION
In conclusion, we have developed a Ru-catalyzed formal
anti-Markovnikov asymmetric hydroamination of allylic alcohols
via a hydrogen borrowing mechanism. For the first time, racemic
secondary allylic alcohols are hydroaminated with various
secondary amines to afford chiral γ-amino alcohols with broad
substrate scope, good yields and excellent enantioselectivities.
The protocol can be performed on a gram scale and could
potentially be used for the synthesis of drug molecules.
Acknowledgements
This research was supported by the National Natural Science
Foundation of China (21773145), Projects for the Academic
Leaders and Academic Backbones, Shaanxi Normal University
(16QNGG008), the 111 project (B14041).
Figure 3. Gram-scale reaction and synthetic applications.
Based on our previous studies[10q, 12] and the literature[11]
,
the mechanism of this asymmetric hydroamination may be
similar to that of the previously reported formal anti-Markovnikov
hydroamination of allylic alcohols.[11-12] As illustrated in Figure 1d, Conflict of interest
the chiral Ru catalyst is likely to dehydrogenate the allylic
alcohol to afford
a Ru-H hydride complex and an α,β-
Some of this research has been included in a Chinese patent
(patent application number: 202010234438.1).
unsaturated ketone intermediate, which undergoes aza-Michael
addition to give a β-amino ketone intermediate. The β-amino
ketone is then reduced by the chiral Ru-H hydride, affording the
chiral γ-amino alcohol product. Preliminary mechanistic studies
were carried out to corroborate the reaction pathway. Hydrogen
gas was detected under the standard hydroamination conditions
of the model reaction with or without the amine substrate (See
section 6.1 in SI). No reaction took place when the OH group of
1a was replaced with a OAc group (See section 6.2 in SI), and
when the deuterium labelled 1a’ was used as substrate, no
deuterium atom was found in the product, indicative of fast H/D
exchange during dehydrogenation /hydrogenation (Figure S1a,
also see section 6.3 in SI). These observations all support the
involvement of a Ru-catalyzed dehydrogenation/hydrogenation
process. Furthermore, the dehydrogenated α,β-unsaturated
ketone intermediate 9 underwent aza-Michael addition with 2a to
give the intermediate 10 in the absence of the Ru catalyst
(Figure S1b, also see section 6.4 in SI). Still further, under the
catalysis of 3c, 10 was reduced to 4a with either the allylic
alcohol 1a or H2 as the hydrogen source, with enantiomeric
excess identical to the model reaction (Figure S1c, also see
section 6.5 in SI; cf. Table 1). Taken together, these studies
suggest that the hydroamination proceeds via a Ru-catalyzed
dehydrogenation /hydrogenation process in cooperation with a
catalyst-free, aza-Michael addition step.
A 1:1 substrate ratio experiment of the model reaction
under the standard reaction conditions, afforded product 4a in
over 50% yield (67% yield, 99% ee), and the recovered
unreacted starting alcohol 1a had an ee value of 29%,
suggesting the existence of both kinetic resolution and dynamic
kinetic resolution during the reaction (See section 6.6 in SI).
Racemization experiment with the enantioenriched 4a and the
time course of yield and ee of the model reaction under the
standard reaction conditions suggest that the amino alcohol
products are stable under the reaction conditions and do not
racemize (See section 6.7 in SI), which might be due to the
intramolecular hydrogen bonding and the increased steric
bulkiness in the products (see above) and the competing
dehydrogenation of allylic alcohol substrates with the products.
Keywords: allylic alcohol • amino alcohol • ruthenium catalyst•
hydrogen borrowing • asymmetric catalysis
[1]
a) S. Kondo, S. Shibahara, S. Takahashi, K. Maeda, H. Umezawa, M.
Ohno, J. Am. Chem. Soc. 1971, 93, 6305-6306; b) D. J. Kempf, H. L.
Sham, K. C. Marsh, C. A. Flentge, D. Betebenner, B. E. Green, E.
McDonald, S. Vasavanonda, A. Saldivar, N. E. Wideburg, W. M. Kati, L.
Ruiz, C. Zhao, L. Fino, J. Patterson, A. Molla, J. J. Plattner, D. W.
Norbeck, J. Med. Chem. 1998, 41, 602-617; c) S. Yasuda, H. Kitagawa,
M. Ueno, H. Ishitani, M. Fukasawa, M. Nishijima, S. Kobayashi, K.
Hanada, J. Biol. Chem. 2001, 276, 43994-44002; d) H. L. Sham, C.
Zhao, L. Li, D. A. Betebenner, A. Saldivar, S. Vasavanonda, D. J.
Kempf, J. J. Plattner, D. W. Norbeck, Bioorg. Med. Chem. Lett. 2002,
12, 3101-3103; e) H. Kakei, T. Nemoto, T. Ohshima, M. Shibasaki,
Angew. Chem. Int. Ed. 2004, 43, 317-320; f) Y. Fujima, M. Ikunaka, T.
Inoue, J. Matsumoto, Org. Proc. Res. Dev. 2006, 10, 905-913.
[2]
[3]
a) S. M. Lait, D. A. Rankic, B. A. Keay, Chem. Rev. 2007, 107, 767-
796; b) M. S. I. El Alami, M. A. El Amrani, F. Agbossou-Niedercorn, I.
Suisse, A. Mortreux, Chem. Eur. J. 2015, 21, 1398-1413.
For selected examples on the synthesis of chiral γ-amino alcohols see:
a) Y. Gao, K. B. Sharpless, J. Org. Chem. 1988, 53, 4081-4084; b) J.
Barluenga, E. Aguilar, S. Fustero, B. Olano, A. L. Viado, J. Org. Chem.
1992, 57, 1219-1223; c) A. R. Haight, T. L. Stuk, M. S. Allen, L.
Bhagavatula, M. Fitzgerald, S. M. Hannick, F. A. J. Kerdesky, J. A.
Menzia, S. I. Parekh, T. A. Robbins, D. Scarpetti, J.-H. J. Tien, Org.
Proc. Res. Dev. 1999, 3, 94-100; d) G. E. Keck, A. P. Truong, Org. Lett.
2002, 4, 3131-3134; e) J.-L. Liang, S.-X. Yuan, J.-S. Huang, W.-Y. Yu,
C.-M. Che, Angew. Chem. Int. Ed. 2002, 41, 3465-3468; f) G. Bartoli, M.
Bartolacci, M. Cortese, E. Marcantoni, M. Massaccesi, R. Pela, L.
Sambri, Eur. J. Org. Chem. 2004, 2004, 2359-2366; g) P. Aschwanden,
L. Kværnø, R. W. Geisser, F. Kleinbeck, E. M. Carreira, Org. Lett. 2005,
7, 5741-5742; h) S. Fustero, D. Jiménez, J. Moscardó, S. Catalán, C.
del Pozo, Org. Lett. 2007, 9, 5283-5286; i) D. Menche, F. Arikan, J. Li,
S. Rudolph, Org. Lett. 2007, 9, 267-270; j) E. Milczek, N. Boudet, S.
Blakey, Angew. Chem. Int. Ed. 2008, 47, 6825-6828; k) D. N. Zalatan, J.
Du Bois, J. Am. Chem. Soc. 2008, 130, 9220-9221; l) H. Geng, W.
Zhang, J. Chen, G. Hou, L. Zhou, Y. Zou, W. Wu, X. Zhang, Angew.
Chem. Int. Ed. 2009, 48, 6052-6054; m) G. T. Rice, M. C. White, J. Am.
Chem. Soc. 2009, 131, 11707-11711; n) R. Millet, A. M. Träff, M. L.
Petrus, J.-E. Bäckvall, J. Am. Chem. Soc. 2010, 132, 15182-15184; o)
H. Geng, X. Zhang, M. Chang, L. Zhou, W. Wu, X. Zhang, Adv. Synth.
Catal. 2011, 353, 3039-3043; p) C. Solé, A. Whiting, H. Gulyás, E.
Fernández, Adv. Synth. Catal. 2011, 353, 376-384; q) A. Träff, R.
Lihammar, J.-E. Bäckvall, J. Org. Chem. 2011, 76, 3917-3921; r) A. D.
J. Calow, A. S. Batsanov, A. Pujol, C. Solé, E. Fernández, A. Whiting,
Org. Lett. 2013, 15, 4810-4813; s) J. S. Lee, D. Kim, L. Lozano, S. B.
Kong, H. Han, Org. Lett. 2013, 15, 554-557; t) J.-N. Zhou, Q. Fang, Y.-
H. Hu, L.-Y. Yang, F.-F. Wu, L.-J. Xie, J. Wu, S. Li, Org. Biomol. Chem.
2014, 12, 1009-1017; u) J. M. M. Verkade, P. J. L. M. Quaedflieg, G. K.
M. Verzijl, L. Lefort, F. L. van Delft, J. G. de Vries, F. P. J. T. Rutjes,
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202009754
Angewandte Chemie International Edition
COMMUNICATION
Chem. Commun. 2015, 51, 14462-14464; v) P. A. Spreider, A. M. Haydl,
M. Heinrich, B. Breit, Angew. Chem. Int. Ed. 2016, 55, 15569-15573; w)
L. Wu, R. Jin, L. Li, X. Hu, T. Cheng, G. Liu, Org. Lett. 2017, 19, 3047-
3050; x) Y.-Q. Zhang, F. Bohle, R. Bleith, G. Schnakenburg, S. Grimme,
A. Gansäuer, Angew. Chem. Int. Ed. 2018, 57, 13528-13532.
a) D. Liu, W. Gao, C. Wang, X. Zhang, Angew. Chem. Int. Ed. 2005, 44,
1687-1689; b) J. Wang, D. Liu, Y. Liu, W. Zhang, Org. Biomol. Chem.
2013, 11, 3855-3861; c) Q. Hu, Z. Zhang, Y. Liu, T. Imamoto, W. Zhang,
Angew. Chem. Int. Ed. 2015, 54, 2260-2264; d) J. Wang, Y. Wang, D.
Liu, W. Zhang, Adv. Synth. Catal. 2015, 357, 3262-3272.
a) S. Ichikawa, S. L. Buchwald, Org. Lett. 2019, 21, 8736-8739; b) Y.
Yang, S.-L. Shi, D. Niu, P. Liu, S. L. Buchwald, Science 2015, 349, 62-
66; c) S.-L. Shi, Z. L. Wong, S. L. Buchwald, Nature 2016, 532, 353-
356; d) R. Y. Liu, S. L. Buchwald, Acc. Chem. Res. 2020, 53, 1229-
1243.
For selected reviews on hydroamination see: a) T. E. Müller, M. Beller,
Chem. Rev. 1998, 98, 675-704; b) M. Nobis, B. Drießen-Hölscher,
Angew. Chem. Int. Ed. 2001, 40, 3983-3985; c) F. Pohlki, S. Doye,
Chem. Soc. Rev. 2003, 32, 104-114; d) P. W. Roesky, T. E. Müller,
Angew. Chem. Int. Ed. 2003, 42, 2708-2710; e) S. Hong, T. J. Marks,
Acc. Chem. Res. 2004, 37, 673-686; f) K. Hii King, Pure Appl. Chem.
2006, 78, 341; g) T. E. Mꢀller, K. C. Hultzsch, M. Yus, F. Foubelo, M.
Tada, Chem. Rev. 2008, 108, 3795-3892; h) K. D. Hesp, M. Stradiotto,
ChemCatChem 2010, 2, 1192-1207; i) J. Hannedouche, E. Schulz,
Chem. Eur. J. 2013, 19, 4972-4985; j) E. Bernoud, C. Lepori, M. Mellah,
E. Schulz, J. Hannedouche, Catal. Sci. Technol. 2015, 5, 2017-2037; k)
M. D. Greenhalgh, A. S. Jones, S. P. Thomas, ChemCatChem 2015, 7,
190-222; l) L. Huang, M. Arndt, K. Gooßen, H. Heydt, L. J. Gooßen,
Chem. Rev. 2015, 115, 2596-2697; m) M. Villa, A. Jacobi von Wangelin,
Angew. Chem. Int. Ed. 2015, 54, 11906-11908; n) V. I. Isaeva, L. M.
Kustov, Top. Catal. 2016, 59, 1196-1206; o) M. T. Pirnot, Y.-M. Wang,
S. L. Buchwald, Angew. Chem. Int. Ed. 2016, 55, 48-57; p) M. D.
Kärkäs, ACS Catal. 2017, 7, 4999-5022; q) C. Lepori, J. Hannedouche,
Synthesis 2017, 49, 1158-1167; r) C. Michon, M.-A. Abadie, F. Medina,
F. Agbossou-Niedercorn, J. Organomet. Chem. 2017, 847, 13-27; s) M.
Patel, R. K. Saunthwal, A. K. Verma, Acc. Chem. Res. 2017, 50, 240-
254.
Young, F. Duarte, T. J. Donohoe, Angew. Chem. Int. Ed. 2019, 58,
12558-12562; n) G. Xu, G. Yang, Y. Wang, P.-L. Shao, J. N. N. Yau, B.
Liu, Y. Zhao, Y. Sun, X. Xie, S. Wang, Y. Zhang, L. Xia, Y. Zhao,
Angew. Chem. Int. Ed. 2019, 58, 14082-14088; o) D. M. J. Cheang, R.
J. Armstrong, W. M. Akhtar, T. J. Donohoe, Chem. Commun. 2020, 56,
3543-3546; p) T. W. Ng, G. Liao, K. K. Lau, H.-J. Pan, Y. Zhao, Angew.
Chem. Int. Ed. 2020, 59, 11384-11389; q) K. Wang, L. Zhang, W. Tang,
H. Sun, D. Xue, M. Lei, J. Xiao, C. Wang, Angew. Chem. Int. Ed. 2020,
59, 11408-11415.
[4]
[5]
[6]
[11] Y. Nakamura, T. Ohta, Y. Oe, Chem. Commun. 2015, 51, 7459-7462.
[12] W. Ma, X. Zhang, J. Fan, Y. Liu, W. Tang, D. Xue, C. Li, J. Xiao, C.
Wang, J. Am. Chem. Soc. 2019, 141, 13506-13515.
[13] The content of part of the research has been filed a Chinese patent.
Patent application number: 202010234438.1.
[14] T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa, K. Murata, E.
Katayama, T. Yokozawa, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1998,
120, 13529-13530.
[15] K. Matsumura, N. Arai, K. Hori, T. Saito, N. Sayo, T. Ohkuma, J. Am.
Chem. Soc. 2011, 133, 10696-10699.
[16] E. Chae, H. Yi, Y. Choi, H. Cho, K. Lee, H. Moon, Bioorg. Med. Chem.
Lett. 2012, 22, 2434-2439.
[7]
For selected reviews on hydrogen borrowing reactions see: 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) C.
Gunanathan, D. Milstein, Science 2013, 341, 1229712; h) Y. Obora,
ACS Catal. 2014, 4, 3972-3981; i) A. Nandakumar, S. P. Midya, V. G.
Landge, E. Balaraman, Angew. Chem. Int. Ed. 2015, 54, 11022-11034;
j) S. Werkmeister, J. Neumann, K. Junge, M. Beller, Chem. Eur. J. 2015,
21, 12226-12250; k) Q. Yang, Q. Wang, Z. Yu, Chem. Soc. Rev. 2015,
44, 2305-2329; l) J. Feng, Z. A. Kasun, M. J. Krische, J. Am. Chem.
Soc. 2016, 138, 5467-5478; m) F. Huang, Z. Liu, Z. Yu, Angew. Chem.
Int. Ed. 2016, 55, 862-875; n) A. Quintard, J. Rodriguez, Chemsuschem
2016, 9, 28-30; o) G. Chelucci, Coord. Chem. Rev. 2017, 331, 1-36; p)
R. H. Crabtree, Chem. Rev. 2017, 117, 9228-9246; q) C. Wang, J. Xiao,
Chem. Commun. 2017, 53, 3399-3411; r) A. Corma, J. Navas, M. J.
Sabater, Chem. Rev. 2018, 118, 1410-1459; s) L. Alig, M. Fritz, S.
Schneider, Chem. Rev. 2019, 119, 2681-2751; t) T. Irrgang, R. Kempe,
Chem. Rev. 2019, 119, 2524-2549; u) B. G. Reed-Berendt, K. Polidano,
L. C. Morrill, Org. Biomol. Chem. 2019, 17, 1595-1607.
[8]
[9]
a) A. Quintard, T. Constantieux, J. Rodriguez, Angew. Chem. Int. Ed.
2013, 52, 12883-12887; b) A. Quintard, J. Rodriguez, Chem. Commun.
2016, 52, 10456-10473; c) M. Roudier, T. Constantieux, A. Quintard, J.
Rodriguez, ACS Catal. 2016, 6, 5236-5244; d) M. Roudier, T.
Constantieux, J. Rodriguez, A. Quintard, Chimia Int. J. Chem. 2016, 70,
97-101.
D. Lichosyt, Y. Zhang, K. Hurej, P. Dydio, Nature Catal. 2019, 2, 114-
122.
[10] For
a review and examples of asymmetric hydrogen borrowing
reactions see: a) D. Hollmann, ChemSusChem 2014, 7, 2411-2413; b)
G. Onodera, Y. Nishibayashi, S. Uemura, Angew. Chem. Int. Ed. 2006,
45, 3819-3822; c) 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; d) A. Eka Putra, Y. Oe, T. Ohta, Eur.
J. Org. Chem. 2013, 2013, 6146-6151; e) O. O. Kovalenko, H.
Lundberg, D. Hübner, H. Adolfsson, Eur. J. Org. Chem. 2014, 2014,
6639-6642; f) Y. Zhang, C.-S. Lim, D. S. B. Sim, H.-J. Pan, Y. Zhao,
Angew. Chem. Int. Ed. 2014, 53, 1399-1403; g) Z.-Q. Rong, Y. Zhang,
R. H. B. Chua, H.-J. Pan, Y. Zhao, J. Am. Chem. Soc. 2015, 137, 4944-
4947; h) M. Peña-López, H. Neumann, M. Beller, Angew. Chem. Int. Ed.
2016, 55, 7826-7830; i) C. S. Lim, T. T. Quach, Y. Zhao, Angew. Chem.
Int. Ed. 2017, 56, 7176-7180; j) L.-C. Yang, Y.-N. Wang, Y. Zhang, Y.
Zhao, ACS Catal. 2017, 7, 93-97; k) P. Yang, C. Zhang, Y. Ma, C.
Zhang, A. Li, B. Tang, J. S. Zhou, Angew. Chem. Int. Ed. 2017, 56,
14702-14706; l) M. Jacolot, S. Moebs-Sanchez, F. Popowycz, J. Org.
Chem. 2018, 83, 9456-9463; m) R. J. Armstrong, W. M. Akhtar, T. A.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202009754
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Anti-Markovnikov hydroamination of racemic allylic alcohols produces chiral γ-amino alcohols, key intermediates for the synthesis of
many drug and biologically active molecules. Driven by a Ru catalyst via a hydrogen borrowing pathway, the reaction features broad
substrate scope (68 examples) and excellent enantioselectivities (up to >99% ee).
6
This article is protected by copyright. All rights reserved.