A highly active catalyst for the hydrogenation of amides to alcohols and amines

Article abstract of DOI:10.1002/anie.201103137

Amide-zing: The reaction between 2 equivalents of Ph₂P(CH ₂)₂NH₂ and cis-[Ru(CH₃CN) ₂(η³-C₃H₅)(cod)]BF₄ (cod=1,5-cyclooctadiene) forms a highly active catalyst precursor for the selective hydrogenation of amides. The reaction proceeds with excellent atom economy, yield, and turnover numbers (TONs) under moderate reaction conditions. The technology offers a greener, practical approach to the use of metal hydride reagents commonly employed in both academia and industry. Copyright

Full text of DOI:10.1002/anie.201103137

DOI: 10.1002/anie.201103137
Homogeneous Catalysis
A Highly Active Catalyst for the Hydrogenation of Amides to Alcohols
and Amines**
Jeremy M. John and Steven H. Bergens*
Alcohols and amines are ubiquitous in the synthesis of
agrochemicals, pharmaceuticals (e.g. protection, deprotec-
tion), flavorings, fragrances, and advanced materials.[1] One
approach to accessing these compounds is through the
reduction of amides. Amides are, however the most stable
carboxylic acid derivative.[2] Consequently, the reduction of
amides typically requires stoichiometric amounts of active
(0.1 mol% [Ru], 08C, 50 atm H2, 9 mol% tBuOK, 17–
57 h).[10] The most active system to date, reported by Milstein
and co-workers, is the dearomatized, bipyridyl-based PNN/
Ru complex (PNN = (2-(di-tert-butylphosphinomethyl)-6-
(diethylaminomethyl)pyridine) that hydrogenates a variety
of secondary amides, and tertiary amides having ether groups
to give the alcohol and amine products (1 mol% [Ru] in THF,
base free, 1108C, 10 atmH2, 48 h).[11]
[3]
[3]
[4]
À
À
À
Al H, B H, or Si H reducing agents that often cause
=
reductive cleavage of the C O bond.
We recently reported the low-temperature preparation
and study of the Noyori ketone hydrogenation catalyst trans-
Numerous heterogeneous catalysts have been developed
to hydrogenate amides. These include copper/chromite sys-
tems that give mixtures of amine products under 350 atm of
H2 at temperatures of 250–4008C.[5] Co-catalysts of Rh or Ru
[Ru((R)-binap)(H)2((R,R)-dpen)] (1).[12] Compound
1 is
remarkably active towards carbonyl reduction. For example,
1 adds acetophenone upon mixing and adds g-butyrolactone
within minutes at À808C to form the alkoxide trans-[Ru((R)-
binap)(H)(OCH(CH3)(Ph))((R,R)-dpen)],[12b] and the corre-
sponding Ru/hemiacetaloxide of g-butyrolactone. The com-
plex 1 also catalyzes the hydrogenation of ethyl hexanoate
under 4 atm H2 below a temperature of 08C,[13] and the
monohydrogenation of meso-cyclic imides at 08C.[10] We
report herein the results of our study of 1 and related
compounds as catalysts for the hydrogenation of amides.
We found that the activity of 1 towards the activated
amides N-methylsulfonylpyrrolidin-2-one (2a) and N-acetyl-
pyrrolidin-2-one (2b) was low to moderate. Compound 2a
was hydrogenated with a turnover number (TON) of approx-
imately 27 to give the ring-opened N-methanesulfonyl amino
alcohol product when using 2 mol% [Ru] in THF (1008C,
50 atm, 20 mol% KOtBu, 39 h) [Eq. (1); Ms = methanesul-
fonyl]. Substrate 2b formed mixtures of pyrrolidine-2-one
(major) and the ring-opened N-acetyl amino alcohol with a
TON of approximately 45 using 2 mol% [Ru] (808C, 50 atm
H2, 20 mol% KN[Si(CH3)3]2, 16 h). N-phenylpyrrolidin-2-one
(2c) was inactive under our reaction conditions.
with Re, W, or Mo hydrogenate amides either by reductive
[6]
=
cleavage of the C O bond (100 atm H2, 160–1808C), or by
selectively hydrogenating primary amides to the correspond-
ing primary amines (20–100 atm H2, 130–1608C).[7]
There are a handful of homogeneous systems that catalyze
the hydrogenation of amides or amide derivatives. The first is
a Ru/triphos system (triphos = 1,1,1-tris(diphenylphosphino-
methyl)ethane) that hydrogenates primary amides with a
=
preference for the reductive cleavage of the C O bond in the
presence of NH3 (40 atm H2, 140–1648C, 14 h).[8] Beginning in
2006, Ikariya et al. reported dihydrogenations of cyclic
imides,[9a,c] N-acylcarbamates, N-sulfonyllactams, N-acyl-
sulfonamides,[9b] N-phenyllactams, and benzamides[9d,e] with
À
reductive cleavage of the C N bond catalyzed by
[Cp*RuCl(PN)] (Cp* = h5-C5(CH3)5, e.g. PN = Ph2P-
(CH2)2NH2) or [Cp*RuCl(LN)] (e.g. LN = 2-C5H4NCH2-
NH2) under the reported reaction conditions (tBuOH or 2-
PrOH, 80–1008C, 30–50 atm, KOtBu 1–2.5 equiv, 2–72 h).
Our group recently reported the enantioselective monohy-
drogenation of meso-cyclic imides to give hydroxy lactams
using trans-[Ru(H)2(binap)(dpen)] (binap = 2,2’-bis(diphe-
nylphosphino)-1,1’-binaphthyl, dpen = 1,2-diphenylethylene-
diamine) and related complexes in THF at low temperatures
[*] J. M. John, Prof. Dr. S. H. Bergens
Department of Chemistry, University of Alberta
Edmonton, Alberta, T6G 2G2 (Canada)
E-mail: steve.bergens@ualberta.ca
[**] This work was supported by the Natural Sciences and Engineering
Research Council of Canada (NSERC), the Government of the
Republic of Trinidad and Tobago (GoRTT), and the University of
Alberta. We gratefully appreciate the assistance of Mark Miskolzie,
Nupur Dabral, and Mickey Richards at the University of Alberta
High Field NMR laboratory and we would like to express our
gratitude to Dr. Satoshi Takebayashi for his advice and numerous
discussions.
These results are in contrast to the high activity of 1
towards the reduction of ketones, esters, and imides in
THF.[10,12,13] We reasoned that catalysts such as 1 are intrinsi-
cally active towards amide hydrogenation, but they decom-
pose[12] at the higher temperaturerequired for this trans-
formation. We hypothesized that tethering the amine and
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[a,b]
Table 2: Hydrogenation of acyclic amides using 5 and KN[Si(CH3)3]2
phosphine groups would maintain activity, and prevent
dissociative loss of the diamine at high temperatures. We
found that reaction between 2 equivalents of Ph2P(CH2)2NH2
(3) and the Ru precursor cis-[Ru(CH3CN)2(h3-C3H5)-
(cod)]BF4 (4; cod = 1,5-cyclooctadiene) in THF at 608C
forms isomers of the p-allyl complex 5 in near-quantitative
yield (in solution) by displacement of the cod and MeCN
ligands [Eq. (2)].[14,15,17]
Entry
Substrate
R
R1
R2
Yield [%][c]
TON
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8 f
8g
8h
8i
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Ph
Ph
Ph
Me
Me
–
H
H
Ph
Me
Me
H
100[d]
96
50
82
50
1000
960
500
820
500
Me
-(CH2)5-
Ph
Me
Ph
Ph
Me
Ph
27
270
100
100
50[e]
70
1000
1000
500
10
8j
700
[a] Performed using in situ prepared catalyst precursor 5. [b] Reaction
conditions: H2 at 50 atm, 1008C, 5/KN[Si(CH3)3]2 =1:40, [Substrate]=
0.626m in THF. [c] Determined by 1H NMR spectroscopy. [d] 72% benzyl
alcohol, 14% benzyl benzoate. [e] Anthracene used as an internal
standard.
Table 1 and Table 2 summarize the results of our amide
hydrogenations using 5 and KN[Si(CH3)3]2 as the added base
in THF. All hydrogenations were carried out with 0.1 mol%
[Ru] , 4–5 mol% KN[Si(CH3)3]2, and 50 atmH2 at 1008C, for
24 hours. To our pleasant surprise, N-phenylpyrrolidin-2-one
(2c) was hydrogenated to give N-phenyl-4-aminobutan-1-ol
in 100% yield, or with a TON of 1000 under these reaction
order is consistent with the differences in the extent of
donation from the lone pair of electrons on the nitrogen atom
to the carbonyl carbon center of these substrates. 1-Benzoyl-
piperidine (8d; entry 4) was more active than 8c (entry 3),
whereas secondary amides were somewhat less reactive than
tertiary amides (entry 5 versus entry 1 and entry 6 versus
entry 3). Similar results were obtained with acyclic acet-
amides. Specifically, the reactivity was on the order of
À
À
conditions (entry 1, Table 1). The N Me (entry 2) and N H
(entry 3) derivatives were much less active than 2c, whereas
À
À
À
N(Ph)2 ꢀ N(Ph)Me > N(Me)2 (entries 7–9). The secon-
À
À
the six-membered N Ph derivative 6 reacted in 100% yield
dary acetamide N(Ph)H 8j (entry 10) was less reactive than
(entry 4). The seven-membered unsubstituted lactam
7
the corresponding tertiary amide (entry 8). The lower reac-
tivity of secondary versus tertiary amides may arise from
reaction of the secondary amide with the added base.
(entry 5) was more reactive than the five-membered lactam
2e (entry 3), as expected from the greater stability of five-
over seven-membered rings.
In preliminary experiments, we found that 5 reacts with H2
(ca. 1 atm) and KN[Si(CH3)3]2 (ca. 3 equiv) in [D8]THF
starting at approximately 08C to form propylene and three
ruthenium monohydrides.[16] The known[17] dichloride
[Ru(Cl)2(Ph2P(CH2)2NH2)2] (11) gives a similar mixture of
monohydride species under these reaction conditions. This
mixture reacts further (ca. 4 atm H2, ca. 10 equiv KN[Si-
(CH3)3]2) at room temperature to generate a symmetrical
dihydride as the major product, which we tentatively assign to
be an isomer of trans-[Ru(H)2(Ph2P(CH2)2NH2)2] (9).[18,19]
Saudan et al. reported that 11 forms an active ester hydro-
genation catalyst with NaOMe as the base in THF.[17] Indeed,
we found that 5 and 11 (0.01 mol%) both hydrogenate 2c
with remarkable TONs of 7120 and 6760, respectively, in the
presence of 5 mol% NaOMe (Table 3).
Table 1: Hydrogenation of lactams using 5 and KN[Si(CH3)3]2.[a,b]
Entry
Substrate
Yield [%][c]
TON
1
2
3
4
5
2c
2d
2e
6
100
5
0
100
23
1000
50
0
1000
230
7
On the basis of prior studies with ketone and ester
substrates and 1,[12,13] we propose the following mechanism for
the hydrogenation of amides with 9 (Scheme 1). The first step
is a bifunctional-type addition of the amide to 9, thus forming
the ruthenium hemiaminaloxide 12 as the net product. Base-
assisted elimination from 12 forms the ruthenium/amide 10,
[a] Performed using in situ prepared catalyst precursor 5. [b] Reaction
conditions: H2 at 50 atm, 1008C, 5/KN[Si(CH3)3]2 =1:50, [Substrate]=
0.626m in THF. [c] Determined by 1H NMR spectroscopy.
The order of reactivity among the acyclic benzamides was and the free hemiaminaloxide 13 which regenerates the base
N(Ph)2 ꢀ N(Ph)Me > N(Me)2 (entries 1–3, Table 2). This
and eliminates aldehyde and H-NR1 . Addition of H2 to 10
À
À
À
2
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Angew. Chem. Int. Ed. 2011, 50, 10377 –10380

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Table 3: Hydrogenation of N-phenylpyrrolidin-2-one using 5 or 11 and
NaOMe.[a,b]
Entry
Catalyst precursor
Yield [%][c]
TON
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1
2
5
11
71.2
67.6
7120
6760
[a] Performed using the isolated catalyst precursor 5. [b] Reaction con-
ditions: H2 at 50 atm, 1008C, 5 or 11/NaOMe=1:500, [Substrate]=
2.08m in THF. [c] Determined by 1H NMR spectroscopy.
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Scheme 1. Proposed mechanism for the hydrogenation of amides.
[10] a) S. Takebayashi, J. M. John, S. H. Bergens, J. Am. Chem. Soc.
2010, 132, 12832; b) S. Takebayashi, S. H. Bergens, PCT Int. Pat.
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regenerates 9 and hydrogenation of the aldehyde forms the
alcohol. Consistent with this mechanism is the formation of
benzyl benzoate by the Tishchenko reaction of benzaldehyde
during the hydrogenation of 8a (entry 1, Table 2).We have
shown that 5 and 11 are remarkably active towards the
hydrogenation of a series of amides without strongly activat-
ing functional groups. Significantly, the commonly inert,
unfunctionalized amide dimethyl acetamide was hydrogen-
ated with TONs of 500, and N-phenylpyrrolin-2-one was
hydrogenated with TONs of up to 7120. Studies on catalyst
variations, the mechanism, and the synthetic scope of these
hydrogenations are underway in our laboratories.
[12] a) R. J. Hamilton, C. G. Leong, G. Bigam, M. Miskolzie, S. H.
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[15] Compound 5 was identified by 1H, 31P, gCOSY, 1H{31P} gCOSY,
1H-31P gHSQC, TROESY, and gTOCSY NMR experiments,
mass spectrometry, and elemental analysis.
Received: May 6, 2011
Revised: June 23, 2011
Published online: August 26, 2011
À
[16] Overlap among the signals corresponding to the arene, N H,
and aliphatic protons in the 1H NMR spectra made a conclusive
identification impossible. Their reactivity with H2, and that they
are formed from 5 and 11 suggests that they are isomers of the
ruthenium/amide [Ru(H)(Ph2P(CH2)2NH2)(Ph2P(CH2)2NH)]
(10).
Keywords: amides · green chemistry · homogeneous catalysis ·
.
hydrogenation · N,P ligands
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Angew. Chem. Int. Ed. 2011, 50, 10377 –10380
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www.angewandte.org 10379

Communications
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April 8th, 2010; d) L. Saudan, Acc. Chem. Res. 2007, 40, 1309.
8.26 ppm (Ru-H, t, J = 14.8 Hz), d = 1.25 ppm, d = 2.43 ppm,
d = 2.73 ppm.
[18] This preliminary assignment is based upon the similarities
[19] Use of 4 as a catalyst precursor, or 5 without added base (both at
10 mol%), did not result in hydrogenation. Use of Ru black
(10 mol%) resulted only in hydrogenation of the arene ring in
2c. It is therefore unlikely that Ru nanoparticles are the active
catalyst in these hydrogenations.
1
between the 31P{1H} and H (hydride) NMR spectra between 9
and 1 (see Ref. [12]). The peaks for compound 9 were assigned
1
using 1H, 31P, gCOSY,
31P gHSQC, and gTOCSY NMR
À
H
experiments. 31P{1H} NMR (161.903 mhz, [D8]THF, 278C):
56.2 ppm (s). 1H NMR (399.951mhz, [D8]THF, 278C): d =
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