Highly Selective, Efficient Deoxygenative Hydrogenation of Amides Catalyzed by a Manganese Pincer Complex via Metal-Ligand Cooperation

Article abstract of DOI:10.1021/acscatal.8b02902

Deoxygenative hydrogenation of amides to amines homogeneously catalyzed by a complex of an Earth-abundant metal is presented. This manganese-catalyzed reaction features high efficiency and selectivity. A plausible reaction mechanism, involving metal-ligand cooperation of the manganese pincer complex, is proposed based on NMR studies and relevant stoichiometric reactions.

Full text of DOI:10.1021/acscatal.8b02902

Subscriber access provided by UNIV OF DURHAM
Letter
Highly Selective, Efficient Deoxygenative Hydrogenation of Amides
Catalyzed by a Manganese Pincer Complex via Metal–Ligand Cooperation
You-Quan Zou, Subrata Chakraborty, Alexander Nerush, Dror
Oren, Yael Diskin-Posner, Yehoshoa Ben-David, and David Milstein
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 30 Jul 2018
Downloaded from http://pubs.acs.org on July 30, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
ACS Catalysis
1
2
3
4
5
6
7
8
9
Highly Selective, Efficient Deoxygenative Hydrogenation of Amides
Catalyzed by a Manganese Pincer Complex via Metal–Ligand Coop-
eration
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
†
†
†,§
†
‡
You-Quan Zou, Subrata Chakraborty, Alexander Nerush, Dror Oren, Yael Diskin-Posner,
†
,†
Yehoshoa Ben-David, and David Milstein*
†
‡
Department of Organic Chemistry and Chemical Research Support, Weizmann Institute of Science, Rehovot
6100, Israel
7
Supporting Information Placeholder
ABSTRACT: Deoxygenative hydrogenation of amides to amines homogeneously catalyzed by a complex of an earth-
abundant metal is presented. This manganese catalyzed reaction features high efficiency and selectivity. A plausible reac-
tion mechanism, involving metal-ligand cooperation of the manganese pincer complex, is proposed based on NMR stud-
ies and relevant stoichiometric reactions.
KEYWORDS: deoxygenative hydrogenation, amide, manganese pincer complex, metal-ligand cooperation, amine
Metal–ligand cooperation (MLC) is a powerful activa-
this context, deoxygenative hydrogenation (reduction) of
amides (C-O bond cleavage) represents a straightforward
method to access the corresponding amines.
tion mode in transition metal catalysis which has fasci-
1
10
nated chemists for many years. It has grown into and will
continue to be a popular and flourishing research field. In
this regard, our group developed a mode of MLC involv-
ing aromatization/dearomatization by metal pincer com-
plexes, which found broad applications in the activation
of C–H, N–H, O–H, B–H, B-B, Si-H, as well as H–H
2
bonds. This novel bond activation mode enables the en-
vironmentally benign, sustainable synthesis of numerous
important and useful chemicals from simple starting ma-
terials. However, in most of those reactions complexes of
precious metals are used. Currently there is a growing
research interest in the development of catalytic reactions
Scheme 1. Transition Metal Catalyzed Deoxygenative
Hydrogenation of Amides to Amines
3
based on complexes of earth-abundant metals. In 2016,
our group reported the manganese catalyzed acceptorless
dehydrogenative coupling of alcohols and amines to al-
Conventional methods for the deoxygenative reduction
of amides to amines are largely based on the use of
(over)stoichiometric amounts of reductants such as lithi-
4
a
dimines. Seminal works employing manganese-based
pincer complexes were subsequently disclosed by the
groups of Beller, Kempe, Kirchner and others, including
1
0
um aluminum hydride (LiAlH ), silanes or boranes.
4
4
b-e,5
the dehydrogenation of alcohols
and hydrogenation
However, these methods suffer from the hazardous re-
ductive agents, tedious work-up procedures and genera-
tion of a large amount of waste. To address these issues,
catalytic deoxygenative reduction of amides using hydro-
gen as the terminal reductant, forming water, is ideal. The
relatively low electrophilicity of the amide carbonyl group
and the competitive C–N bond cleavage (deaminative
reduction) make this transformation more challenging
compared to the hydrogenation of aldehydes, ketones and
esters. While heterogeneously catalyzed deoxygenative
6
7,4f
of ketones, esters and C-N bond hydrogenolysis of am-
ides, as well as conjugate addition of non-activated ni-
8
4
g
triles.
Amine skeletons are prevalent in many biologically im-
portant natural products, pharmaceuticals and agrochem-
icals. They also serve as versatile building blocks in organ-
ic synthesis which can be easily elaborated into various
9
fine and useful complex molecules. In addition, amines
are widely used as dyes, surfactants, anticorrosive agents,
9
11
detergents in industrial production. Given the im-
reduction of amides were reported, they were often
11f-i
11a-b,11f-g
portance of amine compounds, the development of effec-
tive protocols for their synthesis is highly desirable. In
stricken with high pressure,
and poor selectivity.
high temperature
11a,11d-e,
Only few reports of homogene-
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 8
e
ously catalyzed reaction were disclosed during the last
7
8
9
Mn-I
Mn-I
Mn-I
Mn-I
Mn-I
Mn-I
BPh3
m-xylene
m-xylene
dioxane
THF
19
74
23
<1
20
63
1
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
decade (Scheme 1, a). Homogeneously catalyzed reac-
tions are generally attractive due to potential high selec-
tivity and being more amenable for mechanistic under-
standing. In 2007, Cole-Hamilton and co-workers report-
ed a ruthenium-triphos complex-catalyzed hydrogenation
of amides to primary and secondary amines with good to
B(C F )
6
5
3
3
3
3
3
B(C F )
17
6
5
10
B(C
F
)
0
6
5
f
1
1
B(C F )
m-xylene
m-xylene
95
89
95 (89)
75
6
5
f,g
1
2a,b
12
B(C
6
F
5
)
excellent selectivities.
Later, the Klankermayer group
a
t
4
Reaction conditions: 2a (0.2 mmol), Mn cat. (5 mol%),
BuOK (6 mol%), Lewis acid BR (0.2 mmol), H (50 bar) and
solvent (1.0 mL) at 150 C (bath temperature) for 72 hours.
Conversions and yields were determined by GC analysis
using biphenyl as an internal standard; isolated yield is given
in parentheses. 12 mol% of BuOK was used. Reaction was
performed at 130 C. Reaction was performed at 110 C.
B(C F ) (0.3 mmol) was used. Reaction was performed for
synthesized a rationally designed ruthenium-triphos η -
3
2
trimethylenemethane complex and successfully applied it
o
1
2c
to the hydrogenation of lactams. Shortly after, similar
ruthenium-based catalytic systems were disclosed by the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
b
1
2d
12e
groups of Beller and Zhou using Yb(OTf) ·H O and
c
t
d
3
2
BF ·OEt as the additives, respectively. Additionally, the
o
e
o
3
2
Zhou group also described a selective deoxygenative hy-
drogenation of amides catalyzed by an iridium pincer
complex, where B(C F ) was used as the Lewis acid addi-
f
g
6
5 3
48 hours.
6
5 3
1
2f
Our initial studies were focused on examining the fea-
tive. Despite these advances, all the above transfor-
mations are using catalysts based on the precious metals
ruthenium or iridium. The development of novel methods
for the deoxygenative hydrogenation of amides without
noble metals is of great importance.
sibility of the deoxygenative hydrogenation of N-
phenylbenzamide (2a) and optimization of the reaction
conditions for the application to various amides. Encour-
agingly, the hydrogenation of 2a did indeed take place in
the presence of the manganese PNP complex Mn-I (5
mol%) BuOK (6 mol%) and one equivalent of BPh un-
5e
As part of our ongoing research program on sustainable
homogeneous catalysis, we herein report a more envi-
ronmentally benign strategy for the deoxygenative hydro-
genation of amides catalyzed by a pincer complex of
earth-abundant manganese (Scheme 1, b). We envisioned
that the dearomatized manganese complex 1 could heter-
olytically split dihydrogen via MLC, and the resulting
manganese hydride will hydrogenate amides to amines
with the aid of a proper Lewis acid. To the best of our
knowledge, there has hitherto been no report on deoxy-
genative hydrogenation of amides to amines homogene-
ously catalyzed by a complex of a base metal.
t
3
o
der 50 bar H at 150 C in m-xylene, to afford the desired
2
product N-benzylaniline (3a) in 53% GC yield after 72
hours (Table 1, entry 1). The transformation is highly se-
lective and only trace amounts of the C–N bond cleavage
products aniline (< 1%) and benzyl alcohol (< 1%) were
detected by GC (see SI for details). Control experiments
indicated that without manganese complex or Lewis acid
no hydrogenation reaction occurred (entries 2 and 3).
Encouraged by this promising result, we started to opti-
mize the reaction conditions to improve the conversion
4
c,f
and yield. Two manganese PNNH complexes Mn-II and
Mn-III showed lower catalytic performance and pro-
Table 1. Optimizing of the Reaction Conditions
4d
duced the product in 23% and 37% yield, respectively (en-
tries 4 and 5). Lowering the reaction temperatures led to
dramatically decreased conversions and yields (entries 6
and 7). Interestingly, both conversion and yield were in-
creased by using the stronger Lewis acid B(C F ) as the
6
5 3
additive (74% conversion and 63% yield, entry 8). Further
screening the solvents indicated that dioxane and THF
were not suitable reaction media, probably due to their
coordination to B(C F ) (entries 9 and 10). Increasing the
6
5 3
Lewis acid loading to 1.5 equivalents provided the best
results, 95% conversion and 89% isolated yield of the
product 3a (entry 11). Under shorter reaction time (48
hrs), the reaction efficiency was slightly decreased (entry
a
conv.
yield
(%)
entry
Mn
BR3
Solvent
b
b
(
%)
1
2).
Next, we selected the conditions of entry 11 to examine
1
Mn-I
—
BPh3
BPh3
—
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
53
<5
0
53
0
2
3
the generality of this catalytic hydrogenation system by
evaluating a variety of amides. As highlighted in Table 2,
benzamides bearing substituents of different electronic
nature on the N-phenyl group were applicable to this re-
action, and the corresponding secondary amines 3a-3f
were obtained in good to excellent isolated yields (Table
Mn-I
Mn-II
Mn-III
Mn-I
0
c
4
BPh3
BPh3
BPh3
38
45
26
23
37
24
c
5
d
6
2, entries 1-6). The hydrogenation of N-benzyl-, cyclohex-
ACS Paragon Plus Environment

Page 3 of 8
ACS Catalysis
yl- and hexyl- benzamides in 2g-2i also proceeded
1
2
3
4
5
6
7
8
9
9
70
100
100
68
52
70
55
smoothly to give the desired products in good yields (68-
83% yields, entries 7-9). Aliphatic N-phenyl amides such
as N-phenylacetamide (2j), N-phenylpropionamide (2k)
and N-phenylisobutyramide (2l) were compatible with
the optimal conditions, furnishing the products 3j-3l in
52–70% isolated yields (entries 10-12). Notably, the lac-
tams 2-pyrrolidinone (2m), and 2-piperidinone (2n) were
also suitable substrates, and good results were observed
(entries 13-14). Deoxygenation of formamides resulted in
low yields (see SI for details). In order to further extend
the substrate scope, we evaluated the reaction of the ter-
tiary amide 2o; the deoxygenative hydrogenation also
took place to give the fully aliphatic tertiary amine 3o,
albeit in lower conversion (47%) and yield (21%) (entry
1
0
1
1
1
2
75
100
68
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
d
1
3
81
d
1
5). Significantly, all the reactions selectively gave the C-O
14
63
bond cleavage products.
Table 2. Deoxygenative Hydrogenation of Amides 2
to Amines 3 Catalyzed by Mn-I
15
47
21
a
t
Reaction conditions: 2 (0.2 mmol), Mn-I (5 mol%), BuOK
(6 mol%), B(C F ) (0.3 mmol), H (50 bar) and m-xylene (1.0
6
5
3
2
o
b
mL) at 150 C (bath temperature) for 72 hours. Conversions
were determined by GC analysis using biphenyl as an inter-
c
nal standard. Yields of isolated products after flash chroma-
tography. Yields were determined by GC analysis using bi-
phenyl as an internal standard.
d
Iso-
a
conv.
lated
yield
entry
Amide 2
Amine 3
b
(
%)
c
(%)
1
95
98
89
81
2
3
89
69
4
5
6
7
8
97
97
91
86
87
76
83
71
93
90
Scheme 2. (a) Dearomatization of Mn-I, Activation of
H by Complex 1, and Related X-ray Crystal Structures
2
31
and (b) P NMR Spectra
In order to get some insight into the mechanism of this
transformation, we first treated complex Mn-I with 1.2
equivalents of BuOK at room temperature in THF, upon
t
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 8
which the transparent yellow solution immediately
1
2
3
4
—
24
72
48
48
60
80
51
72
83
81
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
changed to a dark brown homogeneous solution (Scheme
2, b; see SI for details) and two sharp AB doublets ap-
—
2
2
0.2 eq.
0.5 eq.
88
peared at δ = 81.03 ( J = 79.9 Hz) and 68.04 ( J = 79.9
P-P
P-P
3
1
Hz) ppm in the P NMR (THF as the solvent), attributa-
ble to complex 1 (Scheme 2, a). Recrystallization of 1 gave
the new N -bridged dinuclear manganese complex 5 (N is
100
1
3
a
t
Reaction conditions: 6 (0.2 mmol), Mn-I (5 mol%), BuOK
(6 mol%), H (50 bar) and m-xylene (1.0 mL) at 150 C (bath
temperature). Conversions were determined by GC analysis
using biphenyl as an internal standard. Yields of isolated
o
2
2
2
b
from the glove box), the only example of a dearomatized
c
N -bridged complex (Scheme 2, a). The bond lengths of
2
C6-C7 and C26-C28 are 1.385 and 1.384 Å , respectively,
products after flash chromatography.
1
4
which clearly indicate double bond characters.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
On the other hand, upon treatment of the above reac-
tion mixture with 1 atm dihydrogen, an orange solution
was formed (Scheme 2, b), generating the new hydride
3
1
1
complex 4, as indicated the P{ H} NMR spectrum in THF
which exhibited a singlet at at δ = 111.77 ppm (see SI for
1
details), and the H NMR spectrum exhibited a hydride
2
resonance at δ = – 4.34 ppm (t, J
= 48.5 Hz). The IR
P-H
spectrum of 4 showed two strong absorption bands at
-
1
1
878.4 (νasym) and 1804.0 cm (ν ). The structure of com-
sym
14
plex 4 was further confirmed by X-ray crystal analysis.
Importantly, when complex 4 was employed as catalyst
for the hydrogenation of amide 2a, full conversion was
observed and the product 3a was isolated in 91% yield
(
Scheme 3).
Scheme 3. Deoxygenative Hydrogenation of Amide 2a
Catalyzed by Complex 4
Scheme 4. Proposed Reaction Mechanism for Man-
ganese-Catalyzed Deoxygenative Hydrogenation of
Amides to Amines
We also examined the manganese complex Mn-I cata-
lyzed hydrogenation of the imine N-benzylideneaniline
1
5
6. As shown in Table 2, the hydrogenation of 6 did occur
under the above optimal hydrogenation conditions, with-
out Lewis acid, resulting in 60% within 24 hours and the
amine 3a was isolated in 51% yield (Table 3, entry 1). Pro-
longing the reaction time to 48 hours, the conversion was
increased to 80% (entry 2). When 0.2 equivalents of
Based on our experimental results and previous work,
we propose a possible reaction mechanism for the Mn-
catalyzed deoxygenative hydrogenation of amides. As we
have shown, in the presence of BuOK, the pincer com-
plex Mn-I undergoes deprotonation to give the dearoma-
tized complex 1, which is very likely the actual catalyst
Scheme 4). Subsequently, complex 1 heterolytically splits
dihydrogen by MLC, generating the aromatized complex
. Then the carbonyl group of the Lewis acid activated
amide 7 may electrophilically attacks the Mn-H moiety of
the coordinatively saturated 4 through an outer-sphere
pathway, leading to formation of the hemiaminal inter-
mediate 9 via transition state 8. Later, the Lewis acid-
assisted dehydration of 9 takes place to produce imine 6
accompanied by the regeneration of the dearomatized
complex 1. Once imine 6 is formed, it may react with the
hydride complex 4 to afford intermediate 11 through tran-
t
B(C F ) was used, the reaction reached 88% conversion
6
5 3
(
within 48 hours (entry 3). Increasing the loading of
B(C F ) to 0.5 equivalents, 100% conversion was recorded
6
5 3
4
and the desired product was isolated in 81% yield (entry
). These results indicate that imine 6 could be an inter-
mediate in the hydrogenation of amide 3a, and Lewis acid
4
1
6
may also accelerate the hydrogenation of the imine.
1
7
Table 3. Hydrogenation of Imine 6 Catalyzed by Mn-I
1
8
1
6
sition state 10 via a similar outer-sphere process. At last,
elimination of the desired product 3a from 11 releases the
complex 1 which then reenters the catalytic cycle.
In conclusion, we have developed the first earth-
abundant-based metal complex for homogeneously cata-
a
conv.
Isolated yield
entry
B(C F )
5 3
t (h)
b
c
6
(
%)
(%)
ACS Paragon Plus Environment

Page 5 of 8
ACS Catalysis
lysed deoxygenative hydrogenation of amides to amines.
Activation and “Green” Catalysis. Acc. Chem. Res. 2011, 44,
588-602. (c) Zell, T.; Milstein, D. Hydrogenation and
Dehydrogenation Iron Pincer Catalysts Capable of Metal–
Ligand Cooperation by Aromatization/Dearomatization. Acc.
Chem. Res. 2015, 48, 1979-1994. (d) Milstein, D. Metal-Ligand
Cooperation by Aromatization-Dearomatization as a Tool in
Single Bond Activation. Phil. Trans. R. Soc. A. 2015, 373,
1
2
3
4
5
6
7
8
9
This synthetically important, highly selective C-O bond
cleavage reaction is catalyzed by a dearomatized pincer
complex of manganese. A plausible catalytic cycle, involv-
ing metal-ligand cooperation, is supported by NMR stud-
ies, stoichiometric reactions, X-ray crystallography and
isolation of plausible intermediates. Further detailed
mechanistic investigations and applications of this meth-
odology are underway in our laboratory, and will be re-
ported in due course.
2
0140189.
(
3) Selected reviews: (a) Bullock, R. M. Catalysis without
Precious Metals; Wiely-VCH: Weinheim, 2010. (b) Acc. Chem.
Res. 2015, special issue on Earth Abundant Metals in
Homogeneous Catalysis. Selected examples: (c) Zuo, W.;
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ASSOCIATED CONTENT
Lough,
A.
J.;
Li,
Y.
F.;
Morris,
R.
H.
Supporting Information. Experimental and spectroscopic
details of the catalytic reactions (PDF). Crystallographic in-
formation files for 4 and 5. (CIF)
Amine(imine)diphosphine Iron Catalysts for Asymmetric
Transfer Hydrogenation of Ketones and Imines. Science 2013,
342, 1080-1083. (d) Sylvester, K. T.; Chirik, P. J. Iron-
Catalyzed, Hydrogen-Mediated Reductive Cyclization of 1,6-
Enynes and Diynes: Evidence for Bis(imino)pyridine Ligand
Participation. J. Am. Chem. Soc. 2009, 131, 8772-8774. (e)
Chakraborty, S.; Brennessel, W. W.; Jones, W. D. A Molecular
Iron Catalyst for the Acceptorless Dehydrogenation and
Hydrogenation of N-Heterocycles. J. Am. Chem. Soc. 2014,
AUTHOR INFORMATION
Corresponding Author
*david.milstein@weizmann.ac.il
§
1
36, 8564-8567. (f) Lin, T.-P.; Peters, J. C. Boryl–Metal Bonds
Alex Nerush deceased on January 25, 2016
Facilitate Cobalt/Nickel–Catalyzed Olefin Hydrogenation. J.
Am. Chem. Soc. 2014, 136, 13672-13683. (g) Yan, T.; Feringa, B.
L.; Barta, K. Iron Catalysed Direct Alkylation of Amines with
Alcohols. Nat. Commun. 2014, 5, 5602. (h) Zhang, G.; Scott, B.
L.; Hanson, S. K. Mild and Homogeneous Cobalt–Catalyzed
Hydrogenation of C=C, C=O, and C=N Bonds. Angew. Chem.,
Int. Ed. 2012, 51, 12102-12106. (i) Rezayee, N. M., Samblanet, D.
C.; Sanford, M. S. Iron-Catalyzed Hydrogenation of Amides
to Alcohols and Amines. ACS Catal. 2016, 6, 6377-6383.
ORCID
David Milstein: 0000-0002-2320-0262
You-Quan Zou: 0000-0002-3580-2295
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the European Research
Council (ERC AdG 692775). D. M. holds the Israel Matz Prof-
essorial Chair of Organic Chemistry. Y.-Q. Z. acknowledges
the Sustainability and Energy Research Initiative (SAERI)
foundation for a research fellowship. We thank Dr Y. Xie for
providing some of the amides and Dr T. W. Janes for proof-
reading the final version of this manuscript.
(4) (a) Mukherjee, A.; Nerush, A.; Leitus, G.; Shimon, L. J. W.;
Ben-David, Y.; Espinosa-Jalapa, N. A.; Milstein, D.
Manganese–Catalyzed
Environmentally
Benign
Dehydrogenative Coupling of Alcohols and Amines to Form
Aldimines and H : A Catalytic and Mechanistic Study. J. Am.
2
Chem. Soc. 2016, 138, 4298-4301. (b) Chakraborty, S.; Das, U.
K.; Ben-David, Y.; Milstein, D. Manganese Catalyzed α-
Olefination of Nitriles by Primary Alcohols. J. Am. Chem. Soc.
2017, 139, 11710-11713. (c) Espinosa-Jalapa, N. A.; Kumar, A.;
Leitus, G.; Diskin-Posner, Y.; Milstein, D. Synthesis of Cyclic
Imides by Acceptorless Dehydrogenative Coupling of Diols
and Amines Catalyzed by a Manganese Pincer Complex. J.
Am. Chem. Soc. 2017, 139, 11722-11725. (d) Kumar, A.;
Espinosa-Jalapa, N. A.; Leitus, G.; Diskin-Posner, Y.; Avram,
L.; Milstein, D. Direct Synthesis of Amides by
Dehydrogenative Coupling of Amines with either Alcohols or
Esters: Manganese Pincer Complex as Catalyst. Angew.
Chem., Int. Ed. 2017, 56, 14992-14996. (e) Das, U. K.; Ben-
David, Y.; Diskin-Posner, Y.; Milstein, D. N-Substituted
Hydrazones by Manganese–Catalyzed Coupling of Alcohols
with Hydrazine: Borrowing Hydrogen and Acceptorless
Dehydrogenation in One System. Angew. Chem., Int. Ed.
REFERENCES
(1) Selected reviews: (a) Grützmacher, H. Cooperating
Ligands in Catalysis. Angew. Chem., Int. Ed. 2008, 47, 1814-
1818. (b) Ikariya, T.; Murata, K.; Noyori, R. Bifunctional
Transition Metal–Based Molecular Catalysts for Asymmetric
Syntheses. Org. Biomol. Chem. 2006, 4, 393-406. (c) van der
Vlugt, J. I. Cooperative Catalysis with First–Row Late
Transition Metals. Eur. J. Inorg. Chem. 2012, 363-375. (d) van
der Vlugt, J. I.; Reek, J. N. H. Neutral Tridentate PNP Ligands
and Their Hybrid Analogues: Versatile Non–Innocent
Scaffolds for Homogeneous Catalysis. Angew. Chem., Int. Ed.
2009, 48, 8832-8846. (e) Khusnutdinova, J. R.; Milstein, D.
Metal–Ligand Cooperation. Angew. Chem., Int. Ed. 2015, 54,
12236-12273.
2018, 57, 2179-2182. (f) Espinosa-Jalapa, N. A.; Nerush, A.;
(
2) Reviews: (a) Milstein, D. Discovery of Environmentally
Shimon, L. J. W.; Leitus, G.; Avram, L.; Ben-David, Y.;
Milstein, D. Manganese–Catalyzed Hydrogenation of Esters
to Alcohols. Chem. Eur. J. 2017, 23, 5934-5938. (g) Nerush, A.;
Vogt, M.; Gellrich, U.; Leitus, G.; Ben-David, Y.; Milstein, D.
Template Catalysis by Metal–Ligand Cooperation. C–C Bond
Formation via Conjugate Addition of Non-activated Nitriles
Benign Catalytic Reactions of Alcohols Catalyzed by
Pyridine-Based Pincer Ru Complexes, Based on Metal–Ligand
Cooperation. Top. Catal. 2010, 53, 915-923. (b) Gunanathan,
C.;
Milstein,
D.
Metal–Ligand
Cooperation
by
Aromatization–Dearomatization: A New Paradigm in Bond
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 8
under Mild, Base-free Conditions Catalyzed by a Manganese
Using a Well–Defined Manganese–PNN Pincer Complex.
Chem. Sci. 2017, 8, 3576-3585.
(9) (a) Roose, P.; Eller, K.; Henkes, E.; Rossbacher, R.; Höke,
H. Amines, Aliphatic. In Ullmann's Encyclopedia of Industrial
Chemistry; Wiley-VCH: Weinheim, 2015. (b) Lawrence, S. A.
Amines:ꢀ Synthesis, Properties and Applications; Cambridge
University Press:ꢀ Cambridge, 2004.
(10) Selected reviews: (a) Smith, A. M.; Whyman, R. Review
of Methods for the Catalytic Hydrogenation of
Carboxamides. Chem. Rev. 2014, 114, 5477-5510. (b) Chardon,
A.; Morisset, E.; Rouden, J.; Blanchet, J. Recent Advances in
Amide Reductions. Synthesis 2018, 50, 984-997. For selected
examples of deoxygenative hydrogenation of amides using
silanes, see: (c) Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller,
M. Zinc-Catalyzed Reduction of Amides: Unprecedented
Selectivity and Functional Group Tolerance. J. Am. Chem.
Soc. 2010, 132, 1770-1771. (d) Reeves, J. T.; Tan, Z.; Marsini, M.
A.; Han, Z. S.; Xu, Y.; Reeves, D. C.; Lee, H.; Lu, B. Z.;
Senanayake, C. H. A Practical Procedure for Reduction of
Primary, Secondary andTertiary Amides to Amines. Adv.
Synth. Catal. 2013, 355, 47-52.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Pincer Complex. J. Am. Chem. Soc. 2016, 138, 6985-6997.
(5) (a) Elangovan, S.; Neumann, J.; Sortais, J.-B.; Junge, K.;
Darcel, C.; Beller, M. Efficient and Selective N-Alkylation of
Amines with Alcohols Catalysed by Manganese Pincer
Complexes. Nat. Commun. 2016, 7, 12641. (b) Mastalir, M.;
Glatz, M.; Pittenauer, E.; Allmaier, G.; Kirchner, K.
Sustainable Synthesis of Quinolines and Pyrimidines
Catalyzed by Manganese PNP Pincer Complexes. J. Am.
Chem. Soc. 2016, 138, 15543-15546. (c) Fu, S.; Shao, Z.; Wang,
Y.; Liu, Q. Manganese-Catalyzed Upgrading of Ethanol into
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1-Butanol. J. Am. Chem. Soc. 2017, 139, 11941-11948. (d) Deibl,
N.; Kempe, R. General and Mild Cobalt-Catalyzed C-
Alkylation of Unactivated Amides and Esters with Alcohols.
J. Am. Chem. Soc. 2016, 138, 10786-10789. (e) Neumann, J.;
Elangovan, S.; Spannenberg, A.; Junge, K.; Beller, M.
Improved and General Manganese-Catalyzed N-Methylation
of Aromatic Amines Using Methanol. Chem. Eur. J. 2017, 23,
5
410-5413. (f) Kallmeier, F.; Dudziec, B.; Irrgang, T.; Kempe,
R. Manganese–Catalyzed Sustainable Synthesis of Pyrroles
from Alcohols and Amino Alcohols. Angew. Chem., Int. Ed.
2017, 56, 7261-7265. (g) Nguyen, D. H.; Trivelli, X.; Capet, F.;
(11) (a) Stein, M.; Breit, B. Catalytic Hydrogenation of Amides
to Amines under Mild Conditions Angew. Chem., Int. Ed.
2013, 52, 2231-2234. (b) Toyao, T.; Siddiki, S. M. A. H.; Morita,
Y.; Kamachi, T.; Touchy, A. S.; Onodera, W.; Kon, K.;
Furukawa, S.; Ariga, H.; Asakura, K.; Yoshizawa, K.; Shimizu,
Paul, J.-F.; Dumeignil, F.; Gauvin, R. M. Manganese Pincer
Complexes for the Base–Free, Acceptorless Dehydrogenative
Coupling of Alcohols to Esters: Development, Scope, and
Understanding. ACS Catal. 2017, 7, 2022-2032.
(6) (a) Elangovan, S.; Topf, C.; Fischer, S.; Jiao, H.;
Spannenberg, A.; Baumann, W.; Ludwig, R.; Junge, K.; Beller,
M. Selective Catalytic Hydrogenations of Nitriles, Ketones,
and Aldehydes by Well–Defined Manganese Pincer
Complexes. J. Am. Chem. Soc. 2016, 138, 8809-8814. (b)
Kallmeier, F.; Irrgang, T.; Dietel, T.; Kempe, R. Highly Active
and Selective Manganese C=O Bond Hydrogenation
Catalysts: The Importance of the Multidentate Ligand, the
Ancillary Ligands, and the Oxidation State. Angew. Chem.,
Int. Ed. 2016, 55, 11806-11809. (c) Bruneau-Voisine, A.; Wang,
D.; Roisnel, T.; Darcel, C.; Sortais, J.-B. Hydrogenation of
K.-i. Rhenium-Loaded TiO2:
A
Highly Versatile and
Chemoselective Catalyst for the Hydrogenation of Carboxylic
Acid Derivatives and the N-Methylation of Amines Using H2
and CO . Chem. Eur. J. 2017, 23, 14848-14859. (c) Mitsudome,
2
T.; Miyagawa, K.; Maeno, Z.; Mizugaki, T.; Jitsukawa, K.;
Yamasaki, J.; Kitagawa, Y.; Kaneda, K. Mild Hydrogenation of
Amides to Amines over a Platinum–Vanadium Bimetallic
Catalyst. Angew. Chem., Int. Ed. 2017, 56, 9381-9385. (d)
Beamson, G.; Papworth, A. J.; Philipps, C.; Smith, A. W.;
Whyman, R. Selective Hydrogenation of Amides using
Ruthenium/Molybdenum Catalysts. Adv. Synth. Catal. 2010,
352, 869-883. (e) Coetzee, J.; Manyar, H. G.; Hardacre, C.;
Cole-Hamilton, D. J. The First Continuous Flow
Hydrogenation of Amides to Amines. ChemCatChem 2013, 5,
2843-2847. (f) Adkins, H.; Wojcik, B. Hydrogenation of
Amides to Amines. J. Am. Chem. Soc. 1934, 56, 247. (g)
Wojcik, B.; Adkins, H. Hydrogenation of Amides to Amines.
J. Am. Chem. Soc. 1934, 56, 2419-2424. (h) Beamson, G.;
Papworth, A. J.; Philipps, C.; Smith. A. M.; Whyman, R.
Selective Hydrogenation of Amides Using Rh/Mo Catalysts. J.
Catal. 2010, 269, 93-102. (i) Beamson, G.; Papworth, A. J.;
Philipps, C.; Smith. A. M.; Whyman, R. Selective
Hydrogenation of Amides Using bimetallic Ru/Re and Rh/Re
Catalysts. J. Catal. 2011, 278, 228-238.
(12) (a) Magro, A. A. N.; Eastham, G. R.; Cole-Hamilton, D. J.
The Synthesis of Amines by the Homogeneous
Hydrogenation of Secondary and Primary Amides. Chem.
Commun. 2007, 3154-3156. (b) Coetzee, J.; Dodds, D. L.;
Klankermayer, J.; Brosinski, S.; Leitner, W.; Slawin, A. M. Z.
Cole-Hamiltion, D. J. Homogeneous Catalytic Hydrogenation
of Amides to Amines. Chem. Eur. J. 2013, 19, 11039-11050. (c)
Meuresch, M.; Westhues, S.; Leitner, W.; Klankermayer, J.
Tailor–Made Ruthenium–Triphos Catalysts for the Selective
Homogeneous Hydrogenation of Lactams. Angew. Chem.,
Int. Ed. 2016, 55, 1392-1395. (d) Cabrero-Antonino, J. R.;
3
Ketones with a Manganese PN P Pincer Pre-catalyst. Catal.
Commun. 2017, 92, 1-4. (d) Garbe, M.; Junge, K.; Walker, S.;
Wei, Z.; Jiao, H.; Spannenberg, A.; Bachmann, S.; Scalone, M.;
Beller,
M.
Manganese(I)–Catalyzed
Enantioselective
Hydrogenation of Ketones Using a Defined Chiral PNP
Pincer Ligand. Angew. Chem., Int. Ed. 2017, 56, 11237-11241.
(
7) (a) Elangovan, S.; Garbe, M.; Jiao, H.; Spannenberg, A.;
Junge, K.; Beller, M. Hydrogenation of Esters to Alcohols
Catalyzed by Defined Manganese Pincer Complexes. Angew.
Chem., Int. Ed. 2016, 55, 15364-15368. (b) van Putten, R.;
Uslamin, E. A.; Garbe, M.; Liu, C.; Gonzalez-de-Castro, A.;
Lutz, M.; Junge, K.; Hensen, E. J. M.; Beller, M.; Lefort, L.;
Pidko, E. A. Non–Pincer–Type Manganese Complexes as
Efficient Catalysts for the Hydrogenation of Esters. Angew.
Chem., Int. Ed. 2017, 56, 7531-7534. (c) Widegren, M. B.;
Harkness, G. J.; Slawin, A. M. Z.; Cordes, D. B.; Clarke, M. L.
A Highly Active Manganese Catalyst for Enantioselective
Ketone and Ester Hydrogenation. Angew. Chem., Int. Ed.
2017, 56, 5825-5828. (d) Widegren, M. B.; Clarke, M. L.
Manganese Catalyzed Hydrogenation of Enantiomerically
Pure Esters. Org. Lett. 2018, 20, 2654-2658.
(
8) Papa, V.; Cabrero-Antonino, J. R.; Alberico, E.;
Spannenberg, A.; Junge, K.; Junge, H.; Beller, M. Efficient and
Selective Hydrogenation of Amides to Alcohols and Amines
ACS Paragon Plus Environment

Page 7 of 8
ACS Catalysis
Alberico, E.; Junge, K.; Junge, H.; Beller, M. Towards a
A.; Lugan, N.; Sortais, J.-B. Chem Commun. 2018, 54, 4302-
4305.
1
2
3
4
5
6
7
8
9
General Ruthenium–Catalyzed Hydrogenation of Secondary
and Tertiary Amides to Amines. Chem. Sci. 2016, 7, 3432-
3442. (e) Yuan, M.-L.; Xie, J.-H.; Zhou, Q.-L. Boron Lewis
Acid Promoted Ruthenium–Catalyzed Hydrogenation of
Amides: An Efficient Approach to Secondary Amines.
ChemCatChem 2016, 8, 3036-3040. (f) Yuan, M.-L.; Xie, J.-H.;
Zhu, S.-F.; Zhou, Q.-L. Deoxygenative Hydrogenation of
(16) B(C F ) can also catalyze the hydrogenation of imines
6
5 3
via frustrated Lewis pairs, see: Heiden, Z. M.; Stephan, D. W.
Aqua, Metal-free Diastereoselective Catalytic Hydrogena-
tions of Imines Using B(C F ) . Chem. Commun. 2011, 47,
6
5 3
5729-5731.
(17) Mukherjee, A.; Srimani, D.; Ben-David, Y.; Milstein, D.
Low–Pressure Hydrogenation of Nitriles to Primary Amines
Catalyzed by Ruthenium Pincer Complexes. Scope and
Mechanism. ChemCatChem 2017, 9, 559-563.
Amides Catalyzed by
Complex. ACS Catal. 2016, 6, 3665-3669.
13) In solution the manganese complex 1 exists as a
a Well–Defined Iridium Pincer
(
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
monomer, and in the solid state it exists as a N –bridged
(18) B(C F ) can reacts with H O to form (C F ) B–OH , see:
2
6
5 3
2
6
5 3
2
dinuclear manganese complex 5. See also: Milstein, D.,
Nerush, A.; Vogt, M.; Mukherjee, A.; Espinosa-Jalapa, N. A.;
Chakraborty, S. Manganese Based Complexes and Uses
Thereof for Homogeneous Catalysis. WO 2017/137984 A1.
Bergquist, C.; Bridgewater, B. M.; Harlan, C. J.; Norton, J. R.;
Friesner, R. A.; Parkin, G. Aqua, Alcohol, and Acetonitrile
Adducts of Tris(perfluorophenyl)borane:ꢀ Evaluation of
Brønsted Acidity and Ligand Lability with Experimental and
Computational Methods. J. Am. Chem. Soc. 2000, 122, 10581-
10590.
2
017.
14) See supporting information for the detailed X-ray
strcuture.
15) Manganese catalyzed redcutive amination of aldehydes
was reported, see: Wei, D.; Bruneau-Voisine, A.; Valyaev, D.
(
(
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 8
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
ACS Paragon Plus Environment