Selective Room-Temperature Hydrogenation of Amides to Amines and Alcohols Catalyzed by a Ruthenium Pincer Complex and Mechanistic Insight

Article abstract of DOI:10.1021/acscatal.0c01406

We report a room-temperature protocol for the hydrogenation of various amides to produce amines and alcohols. Compared with most previous reports for this transformation, which use high temperatures (typically, 100-200 °C) and H2 pressures (10-100 bar), this system proceeds under extremely mild conditions (RT, 5-10 bar of H2). The hydrogenation is catalyzed by well-defined ruthenium-PNNH pincer complexes (0.5 mol %) with potential dual modes of metal-ligand cooperation. An unusual Ru-amidate complex was formed and crystallographically characterized. Mechanistic investigations indicate that the room-temperature hydrogenation proceeds predominantly via the Ru-N amido/amine metal-ligand cooperation.

Full text of DOI:10.1021/acscatal.0c01406

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Letter
Selective Room-Temperature Hydrogenation of Amides to Amines and
Alcohols Catalyzed by a Ruthenium Pincer Complex and Mechanistic Insight
Sayan Kar, Michael Rauch, Amit Kumar, Gregory Leitus, Yehoshoa Ben-David, and David Milstein
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01406 • Publication Date (Web): 21 Apr 2020
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Selective Room-Temperature Hydrogenation of Amides to Amines and Al-
cohols Catalyzed by a Ruthenium Pincer Complex and Mechanistic Insight
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Sayan Kar,† Michael Rauch,† Amit Kumar,†,# Gregory Leitus,‡ Yehoshoa Ben-David,† and David Mil-
stein*,†
†Department of Organic Chemistry, and ‡Department of Chemical Research Support, Weizmann Institute of Science, Re-
hovot 76100, Israel
Supporting Information Placeholder
Saito and co-workers have reported an example of Ru-catalyzed dime-
ABSTRACT: We report a room temperature protocol for the hy-
drogenation of various amides to produce amines and alcohols.
Compared to the most previous reports for this transformation,
which use high temperatures (typically, 100–200 oC) and H2 pres-
sures (10-100 bar), this system proceeds under extremely mild con-
ditions (RT, 5-10 bars of H2). The hydrogenation is catalyzed by
well-defined ruthenium-PNNH pincer complexes (0.5 mol%) with
potential dual modes of metal-ligand cooperation. An unusual Ru-
amidate complex was formed and crystallographically character-
ized. Mechanistic investigations indicate that the room-tempera-
ture hydrogenation proceeds predominantly via the Ru-N am-
ido/amine metal-ligand cooperation.
o
thylformamide hydrogenation at 60 C under high H2 pressure of 80
bars,6k but higher temperature (120 oC) was required at lower H2 pres-
sures (20 bars) to obtain similar yields (60%). Langer and co-workers
reported examples of amide hydrogenation at 70 oC with an iron
complex using high catalyst loading (10 mol%) at 50 bar H2;6g although
this interesting system exhibited limited scope and required 100 oC for
completion at lower catalyst loadings (2 mol%). Recently, Beller and co-
workers reported a Mo-pincer catalyzed amide hydrogenation at 80 oC,
but this system employed high H2 pressure (50 bar) and the substrate
scope was synthetically limited to N-methylphenylformamides.6l Ber-
gens reported asymmetric hydrogenolysis of some specific functional-
ized α-phenoxy amides at RT and low pressure, but the system requires
high catalyst loading (10 mol%) and more than stoichiometric amounts
of strong base (120-250 mol% of t-BuOK/i-PrONa) for effective catal-
ysis.6p
KEYWORDS: amide, hydrogenation, metal-ligand co-
operation, ruthenium-pincer, room-temperature, ruthenium ami-
date complex
Scheme 1. Two possible pathways of amide hydrogenation
Reduction of the amide group has useful applications in diverse areas of
chemical transformations including synthesis of amines, alcohols, pep-
tide chemistry, total synthesis, CO2 recycling and others.1-2 The tradi-
tional methods to reduce amides are non-catalytic and use stoichio-
metric amounts of hydride reducing agents, thus producing stoichio-
metric amount of waste.3 In this context, development of efficient cata-
lytic hydrogenation systems for their reduction is desirable.4 While hy-
drogenations of amides have been reported, they are more challenging
than that of most other carboxylic derivatives due to the low electro-
philic character of the amide carbonyl group.5
Amide hydrogenation can proceed either via C-N bond cleavage or by
C-O bond cleavage (Scheme 1).5a, 5b We are particularly interested in
the C-N bond cleavage pathway, which is challenging due to the water
losing tendency of the hemiaminal intermediate to form imine. The first
example of amide hydrogenation with C-N bond cleavage appeared in
20106a followed by reports of several other research groups.6 Hydro-
genation and dehydrogenative formation of the amide bond has also
been instrumental in the recent development of promising liquid or-
ganic hydrogen carrier (LOHC) systems based on alcohols and amines.7
However, the reported hydrogenation reactions require harsh reaction
conditions (typically 100-150 oC and/or 10-100 bars of H2 pressure). In
this regard, amide hydrogenation protocols to form amines and alcohols
under mild conditions are clearly required. Development of such proto-
cols would also facilitate the development of low-temperature amide
based LOHC systems as well as low-temperature CO2 recycling to
methanol systems.8
As a part of our ongoing research endeavor, we seek to develop metal
complexes to facilitate (de)hydrogenation reactions under mild condi-
tions. To this extent, we have reported a new class of pincer complexes
(based on PNNH ligands) where dual modes of metal ligand coopera-
tion (MLC) are possible (via ligand dearomatization and metal amido
bond formation) (Figure 1).7e, 9 Here, we report a system for room tem-
perature amide hydrogenation to amines and alcohols catalyzed by the
Ru-PNNH complexes at low catalyst loading (0.5 mol%) under low H2
pressures (5-10 bars).
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Reaction conditions: benzanilide (0.5 mmol), Cat. (0.5 mol%), t-
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BuOK (2 mol%), THF (3 mL), H2 (10 bars at RT), T (as specified,
bath temperature), t (as specified). aConversions and yields are de-
b
termined by GC with mesitylene as an internal standard. RT =
Room Temperature (19-24 oC)
Subsequently, we explored the substrate scope of this catalytic hydro-
genation of amides undermild conditions (Table 2). Several substituted
benzanilides were quantitatively converted to the corresponding alcohol
and aniline at RT (under 10 bars H2) with catalyst Ru-2 (entries 1-6).
Formamides, such as N-(4-chlorophenyl)formamide, N-(4-
methylphenyl)formamide can also be hydrogenated at room tempera-
ture to the corresponding amine and methanol (entry 7-8). Other am-
ides, such as N-acetylmorpholine, N,N-diphenylbenzamide, N-acety-
laniline, N-hexylbenzamide, N-phenyloctanamide, N-formylabenzyla-
mine, and N-heptyloctanamide were hydrogenated at either RT or at a
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Figure 1. Amide hydrogenation reported here as compared to pre-
vious reports
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We started our investigation with benzanilide as the model substrate
(
Table 1). When benzanilide in THF was subjected to hydrogenation
(10 bars of H2) at 45 oC with complex Ru-PNNtBuH (Ru-1; 0.5 mol%)
as the pre-catalyst in the presence of catalytic t-BuOK (2 mol%), 67% of
amide conversion was observed by GC after 20 h (entry 1). We observed
the formation of benzyl alcohol and aniline as the reaction products by
GC-MS, revealing the C-N bond cleavage to be the favorable pathway
under the reaction conditions. Changing the N-substitution of the cata-
lyst from t-Bu to benzyl group (Ru-2), the catalytic activity increased
even further, and complete conversion of the amide to the amine and
alcohol was observed after 20 h (entry 2). However, changing the P sub-
stitution of the PNNH ligand from t-Bu to Ph (Ru-3) resulted in a sig-
nificant decrease in the catalytic activity (entry 3). The traditional Ru-
PNNEt catalyst Ru-4, lacking a N-H bond, was unable to efficiently cat-
alyze the hydrogenation at 45 oC (entry 4). With Ru-2, the hydrogena-
tion can proceed to completion within 20 h even at the lower tempera-
o
slightly elevated temperature of 35-45 C (entries 9-15), which is still
significantly lower than the hydrogenation temperature reported previ-
ously with other catalysts.
Table 2. Hydrogenation of various amides at or near RT
En-
try
Substrate
T
Conv (%)a
2
3
(%)a
(oC)
(%)a
o
ture of 35 C (entry 5). Furthermore, full conversion of benzanilide to
1
2
3
4
5
RT 97
RT 99
RT 99
RT 98
RT 99
91
97
92
97
97
93
98
92
95
96
o
benzyl alcohol and aniline can be obtained even at RT (19-24 C), alt-
hough a longer reaction time (68 h) is required (entry 6-7). Toluene is
not as good a solvent as THF for this hydrogenation, possibly due to the
limited solubility of benzanilide in toluene (entry 8).
Table 1. Optimization of catalytic hydrogenation of ben-
zanilide
6
7
RT 97
RT 99
92
89
95
74b,c
8
RT 89
68b,c
72b,c
87
95
En- Cat.
try
T
t
Solvent Conv. 2a
3a
(oC) (h)
(%)a
67
99
20
3
(%)a (%)a
9d
RT 99
RT 99
1
2
3
4
5
6
7
8
Ru-1
Ru-2
Ru-3
Ru-4
Ru-2
Ru-2
Ru-2
Ru-2
45
45
45
45
35
20 THF
63
94
14
3
62
91
12
2
20 THF
20 THF
20 THF
20 THF
10
11
12
13
98
98
89
62
93
81b,c
63
99
52
97
79
95
49
91
73
91
47
93
75
35
35
35
92
65
97
RTb 20 THF
RT 68 THF
RT 68 Tolu-
ene
89
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48b,c
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Reaction conditions: amide (0.5 mmol), Ru-2 (0.5 mol%), t-
BuOK (2 mol%), THF (3 mL), H2 (10 bars at RT), T (as specified),
t (68 h). aConversions and yields were determined by GC with me-
sitylene as an internal standard. Products were characterized by
GC-MS. yield determined by H NMR; yields of methanol and
ethanol are lower than that of the corresponding amine due to vol-
atility. dwith catalyst Ru-1 (0.5 mol%), H2 (5 bar), t (20 h).
b
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Next, we carried out mechanistic investigations to further understand
the high catalytic activity of the Ru-PNNH complexes compared to the
traditional PNNEt complex Ru-4. Upon addition of 2 equiv. of t-BuOK
to a solution of complex Ru-1 (dissolved in THF), an intensely purple-
colored solution of the anionic ruthenium enamido complex Ru-1A was
formed.9d Upon addition of two equiv. of benzanilide to this solution,
the intense purple color disappeared to produce a light-green solution,
and the 31P NMR spectrum exhibited only a single peak at 108.5 ppm
(Figure S13). This is due to the formation of the ruthenium amidate
complex Ru-1B, which was characterized by 1H, 31P and 13C NMR spec-
troscopy (Scheme 2a, Figure S8-S11) and a single crystal X-ray diffrac-
tion study (see SI). As exhibited by the crystal structure, the amidate lig-
and displays κ1-O binding to the Ru metal center, which is uncommon
for late transition metal complexes and, to the best of our knowledge, has
not been observed previously in ruthenium amidate complexes.10 The
κ1-O geometry is also characterized by elongated C-O bond length
(1.279 Å) and shortened C-N bond length (1.307 Å) of the amidate lig-
and as compared to free benzanilide (1.227 Å and 1.363 Å, respectively,
for C-O and C-N bond).11 Furthermore, the coordinated (E) isomer of
κ1-O Ru-1B was observed in the structure, which is rare in any late tran-
sition metal κ1-O amidate complex due to steric reasons.10 Interestingly,
the N-H proton of the PNNH ligand and the N atom of the amidate lig-
and are aligned in close spatial proximity (2.123 Å) with the possibility
of a hydrogen bonding interaction, thus providing additional stability to
Formation of the amidate complex, while interesting, is off-cycle and
may also somewhat decrease the catalytic efficiency in the hydrogena-
tion of the secondary amides. Ru-1B undergoes rapid dissociation and
reassociation of the amide in solution, as verified by an amide exchange
experiment (Figure S20). Under 5 bars of H2 pressure, complex Ru-1B
is in equilibrium with the dihydride complex Ru-1C (Scheme 2a,
Scheme S1). This equilibrium favors the amidate complex Ru-1B (Fig-
ure S13, panel 4) The equilibrium can also be indirectly observed in the
.
presence of D2, in which case rapid suppression of the N-H proton and
the P-CH2 proton of Ru-1B was observed due to H/D scrambling (Fig-
ure S18-S19). To probe the resting state of the catalyst during the reac-
tion, we conducted a control catalytic hydrogenation experiment in an
NMR tube with Ru-1B as catalyst using 5 equiv. of benzanilide substrate
under 5 bars H2. During the reaction progress at 45 oC, only the amidate
complex Ru-1B was observed in the solution while the dihydride com-
plex was not observed (Figure S14). Thus, complex Ru-1B acts as the
catalytic resting state during the reaction.
Returning to the reactivity of the enamido complex Ru-1A, addition of
a substrate lacking a N-H proton, such as N-acetylmorpholine, the solu-
tion of complex Ru-1A remained purple even after the addition of 4
equiv. of amide. No formation of any new complex was observed by
NMR spectroscopy. Pressurizing with 5 bars of H2, immediate for-
mation of the dihydride complex was observed at RT (Scheme 2c; Fig-
ure S16). The dihydride peaks remained the major peak in both 31P and
1H NMR spectra until completion of the hydrogenation, indicating that
the reaction of the amide with the dihydride complex is the rate-deter-
mining step in the catalytic cycle (vide infra, Scheme 3).
1
the Ru-1B. Indeed, in the H NMR spectrum of Ru-1B, the chemical
shift of the N-H proton is strongly downfield shifted (~10.5 ppm), indi-
cating hydrogen bonding even in solution (Figure S8). The hydrogen
bonding is crucial to the formation of the κ1-O (E)-amidate complex as
the analogous amidate complex of Ru-4 lacking an N-H bond, was not
observed under similar conditions (Scheme 2b). Notably, a somewhat
similar amidate complex has been observed by Bernskoetter, Hazari and
co-workers with Fe-PNP system, although with κ1-N coordination.6i
Scheme 3. Plausible mechanistic cycle
Scheme 2. Mechanistic reactions
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considerably lower temperatures (<50 oC) compared to the existing
ones. Both avenues are currently being explored in our group.
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AUTHOR INFORMATION
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Corresponding Author
david.milstein@weizmann.ac.il
8
9
Present address:
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#
Amit Kumar, School of Chemistry, University of St. Andrews,
North Haugh, St. Andrews, KY169ST, Scotland, UK.
Notes
The authors declare no competing financial interests.
Crystallographic data for the structures in this paper have been de-
posited with the Cambridge Crystallographic Data Centre, CCDC,
12 Union Road, Cambridge CB21EZ, UK. Copies of the data can
be obtained free of charge on quoting the depository numbers
CCDC- 1992019 (Fax: +44-1223-336-033; E-Mail: de-
posit@ccdc.cam.ac.uk, http://www.ccdc.cam.ac.uk)
Based on these insights and prior investigations reported, we propose a
catalytic cycle as depicted in Scheme 3.6a, 6k, 9a, 12 For amides bearing an
N-Hproton, the catalytic resting state is the amidate complex Ru-XB. In
the presence of H2, Ru-XB forms the dihydride Ru-XC, which through
hydride attack on the amide carbonyl group and proton abstraction of
the N-H group of the PNNH ligand forms the hemiaminal, along with
the intermediate complex Ru-XD. This step can also occur via proton
abstraction from the CH2 group of the P-side arm instead of the N-H
group (to generate Ru-XD’). However, this pathway does not signifi-
cantly contribute to the overall hydrogenation at lower temperatures
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
General information and experimental details (PDF)
(RT to 45 oC) (compare the hydrogenation activity of Ru-1
/
Ru-2 with
that of Ru-4). It is likely that the acidic nature of the N-H proton of
PNNH ligand assists in lowering the energy requirement of this rate-de-
termining step, thus allowing the hydrogenation to proceed even at RT
via the amido pathway. This can also explain the higher catalytic activity
of Ru-2 compared to Ru-1, where the Bn substitution of the N donor
atom makes the ligand N-H of Ru-2 less basic as compared to Ru-1 with
t-Bu group in the N atom. Alternatively, the lower steric bulk of the ben-
zyl group can also contribute to the observed increased hydrogenation
rate of Ru-2 compared to Ru-1. Subsequently, the hemiaminal quickly
binds to the ruthenium center to form the hemiaminoxy complex Ru-
XE, which, through a proton abstraction from the ligand, releases an
amine molecule with concomitant formation of the aldehyde complex
Ru-XF (or Ru-XF’). Dissociation of the weakly coordinating aldehyde
from Ru center, followed by the H2 splitting across the Ru-N bond gen-
erates the dihydride complex Ru-XC. Outer-sphere hydride transfer
ACKNOWLEDGMENT
This research was supported by the European Research Council
(ERC AdG 692775). D.M. holds the Israel Matz Professorial Chair
of Organic Chemistry. S.K. acknowledge the Sustainability and En-
ergy Research Initiative (SAERI) of the Weizmann Institute of Sci-
ence for a research fellowship. M.R. acknowledges the Zuckerman
STEM Leadership Program for a research fellowship.
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