Iron-Catalyzed Hydrogenation of Amides to Alcohols and Amines

Article abstract of DOI:10.1021/acscatal.6b01454

This article describes the iron-catalyzed hydrogenation of unactivated amides. Under the optimal conditions, a PNP-ligated Fe catalyst affords 25-300 turnovers of products derived from C-N bond cleavage. This reaction displays a broad substrate scope, including a variety of 2° and 3° amide substrates. The reaction progress of N,N-dimethylformamide hydrogenation has been monitored in situ using Raman spectroscopy. This technique enables direct comparison of the relative activity of the Fe-PNP catalyst to that of its Ru analogue. Under otherwise identical conditions, the Fe and Ru catalysts exhibit rates within a factor of 2.

Full text of DOI:10.1021/acscatal.6b01454

Research Article
pubs.acs.org/acscatalysis
Iron-Catalyzed Hydrogenation of Amides to Alcohols and Amines
Nomaan M. Rezayee, Danielle C. Samblanet, and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
*
S Supporting Information
ABSTRACT: This article describes the iron-catalyzed hydro-
genation of unactivated amides. Under the optimal conditions,
a PNP-ligated Fe catalyst affords 25−300 turnovers of
products derived from C−N bond cleavage. This reaction
displays a broad substrate scope, including a variety of 2° and
3
° amide substrates. The reaction progress of N,N-
dimethylformamide hydrogenation has been monitored in
situ using Raman spectroscopy. This technique enables direct
comparison of the relative activity of the Fe-PNP catalyst to that of its Ru analogue. Under otherwise identical conditions, the Fe
and Ru catalysts exhibit rates within a factor of 2.
KEYWORDS: iron catalysis, amide hydrogenation, kinetics, bifunctional catalysis, pincer complexes, homogeneous catalysis
INTRODUCTION
The hydrogenation of carboxylic acid derivatives represents an
atom-economical reduction process with potential applications
choice of supporting ligands. Scheme 2a shows one of the
mildest and most general reported examples, involving catalyst
Ru-1.
We sought to develop an analogous Fe-catalyzed hydro-
genation of unactivated amides and to conduct a detailed
■
29
1
,2
in both industrial and academic settings. The vast majority of
homogeneous catalysts for these transformations contain
second- or third-row transition metals (e.g., Ru, Rh, Pd,
3
−5
Pt). There are many fewer examples of the hydrogenation of
Scheme 2. Examples of Ru- and Fe-Catalyzed Amide
Hydrogenation
carboxylic acid derivatives using earth-abundant first-row metal
6
,7
catalysts. Recent efforts toward this goal have focused on Fe-
8
−11
based catalysts for the hydrogenation of aldehydes,
8
−16
17−21
ketones,
and esters.
However, analogous Fe-catalyzed
hydrogenations of less electrophilic amide derivatives remain
22,23
largely unexplored.
These weakly electrophilic substrates
are expected to be particularly challenging for Fe catalysts, due
to the anticipated lower hydricity of first-row metal hydrides in
24,25
comparison to their second- and third-row counterparts.
Classical methods for amide hydrogenation require the use of
stoichiometric reductants such as lithium aluminum hydride
3
(
LAH) or samarium iodide (SmI ). These reductions occur
2
with either C−O or C−N bond scission to yield distinct sets of
3
products (Scheme 1). Typically, LAH yields the C−O bond
26,27
cleavage product,
scission.
while SmI is selective for C−N bond
2
2
8
The transition-metal-catalyzed hydrogenation of amides
represents a mild alterative to LAH- or SmI -mediated
2
processes. Recent reports have described homogeneous Ru
29−43
catalysts for this transformation
and have demonstrated
that selective C−N cleavage can be achieved by an appropriate
Scheme 1. Pathways for Amide Reduction
Received: May 23, 2016
Revised: August 15, 2016
©
XXXX American Chemical Society
6377
DOI: 10.1021/acscatal.6b01454
ACS Catal. 2016, 6, 6377−6383

ACS Catalysis
Research Article
investigation of catalysts, conditions, and scope. Furthermore,
we sought to benchmark the best Fe catalyst to its second-row
congener. At the start of our investigation, there were no
reported examples of homogeneous Fe-catalyzed amide hydro-
genation. Two very recent papers have described amide
hydrogenation to yield C−N bond scission products using
Table 1. Optimization of Fe-2-Catalyzed DMF
Hydrogenation
a
2
2
23
temp
(°C)
H
2
(bar)
catalysts Fe-1 and Fe-2c. However, these methods suffer
entry
[Fe]
base (mol %)
yield (%) TON
2
2,23
from a limited substrate scope,
modest TONs (up to
1
2
3
4
5
6
7
8
9
Fe-2a none
Fe-2a K PO (8.33)
130
130
130
110
110
110
110
110
110
110
110
110
110
50
50
50
50
20
20
20
20
20
20
20
20
20
63
>99
>99
>99
59
96
78
47
8
189
300
300
300
177
288
244
140
23
2
2,23
50),
and/or forcing conditions (140 °C, 60 bar of H ;
Scheme 2b). We demonstrate herein that Fe-PNP -BH (Fe-
2
2
2
Cy
3
4
4
Fe-2a K PO (1.66)
3
4
2a) is an effective catalyst for the hydrogenation of unactivated
Fe-2a K PO (1.66)
3
4
amides. These transformations selectively afford C−N cleavage
products, and many substrates can be hydrogenated within 3 h
at 110 °C. Further, we demonstrate that Fe-2a catalyzes this
reaction with an initial rate that is within a factor of 2 of that for
its Ru analogue (Ru-2a), under otherwise identical conditions.
Fe-2a none
Fe-2a K PO (1.66)
3
4
Fe-2a NEt (1.66)
3
Fe-2a K CO (1.66)
2
3
Fe-2a NaOEt (1.66)
t
1
0
Fe-2a KO Bu (1.66)
7
20
RESULTS AND DISCUSSION
11
Fe-2a KHMDS (1.66)
Fe-2b K PO (1.66)
4
11
■
1
2
63
2
189
7
3
3
4
4
On the basis of our ongoing interest in the reduction of C-1
44−47
13
Fe-2c
K
PO
(1.66)
starting materials,
we initially focused on the Fe-catalyzed
a
Conditions: 3.0 mmol of DMF, 10 μmol of [Fe], 2 mL of THF, 3 h
hydrogenation of N,N-dimethylformamide (DMF). Fe-2
derivatives were selected as catalysts on the basis of literature
precedent for the use of related Ru and Fe complexes for
in a 45 mL high-pressure Parr vessel with research grade H . Yields
2
1
and TONs are based on CH OH and were determined by H NMR
3
spectroscopy.
1
7,18,21,46,48−53
various CO hydrogenation reactions.
We first
examined the hydrogenation of DMF and N-formylmorpholine
using 1 mol % of Fe-2a, 25 mol % of K PO , and 50 bar of H
2
3
4
54
at 130 °C (Tables S2 and S3 in the Supporting Information).
In our initial trials, this reaction proved to be highly
irreproducible, with yields fluctuating between 0 and 99%
over >10 runs. After an exhaustive investigation, we identified
the purity of the H as the origin of the poor reproducibility.
2
This issue was resolved by changing from ultrahigh-purity H2
We next examined the scope of Fe-2a-catalyzed hydro-
genation of formamides (Table 2). The tertiary alkyl and aryl
formamides N-formylmorpholine, and N,N-diphenylformamide
underwent hydrogenation in quantitative yield and with >95%
selectivity for C−N cleavage (entries 1 and 2). Secondary aryl
formamides were also viable substrates, affording 57−95%
yields of the C−N cleavage products under the standard
conditions (entries 3−7). The highest yields were obtained
with substrates bearing electron-neutral or -withdrawing
substituents on the aromatic ring (compare entry 4 to entries
(
99.999%) to research grade H (99.9999%), which resulted in
2
consistent and reproducible results (variations in yield were
typically ±5%; see the Supporting Information for complete
details).
Using research grade H (50 bar) and 0.33 mol % of Fe-2a at
2
1
30 °C, we obtained a 63% yield of CH OH after 3 h, with high
3
(
>99%) selectivity for C−N cleavage (Table 1, entry 1). The
addition of base is known to promote metal-catalyzed
5
5−58
hydrogenations,
in a related Ru-catalyzed hydrogenation of DMF. Similarly,
the addition of K PO (25 equiv relative to Fe) to the Fe-2a-
and K PO proved particularly effective
3 4
4
6
3
and 6). Substitution at ortho sites on the arene ring was well-
3
4
tolerated (entries 5 and 7). Aryl bromides were compatible with
the reaction conditions, and no dehalogenation products were
detected. Lower yields were observed with 2°-alkyl and 1°-
formamides (entries 8 and 9). These reactivity trends are
comparable to those reported in related Ru-catalyzed amide
catalyzed hydrogenation of DMF under otherwise identical
conditions boosted the yield to >99% (entry 2). Further
optimization revealed that the base loading, temperature, and
H pressure can be decreased while maintaining similar yield
2
37,38,61
(
entries 3−6). A survey of organic and inorganic bases revealed
hydrogenation reactions.
59
K PO as the optimal base for DMF hydrogenation. Overall,
Alkyl- and aryl-substituted amides often required more
forcing conditions in comparison to those for the formamides;
however, after some reoptimization, they also underwent
selective reduction in modest to high yields (Table 3). For
example, N-phenyl- and N,N-diphenylacetamide both afforded
quantitative conversion and high yields of ethanol and the
3
4
under the optimized conditions (0.33 mol % of Fe-2a, 1.66 mol
of K PO , 20 bar of H , 110 °C, 3 h), the reaction proceeded
%
3
4
2
in 96% yield (288 turnovers, entry 6).
The alternative Fe catalysts Fe-2b (entry 12) and Fe-2c
(
entry 13) afforded significantly lower yields under otherwise
identical conditions (63% and 2%, respectively). These results
corresponding amine at 110 °C with 30 bar of H and 2 mol %
2
are particularly noteworthy, since Beller has shown that Fe-2c
of Fe-2a (entries 1 and 2). Notably, N-phenylacetamide was
21,60
22
has higher activity than Fe-2a for ester hydrogenation.
Furthermore, Fe-2c has recently been disclosed for the
reported to be unreactive with catalyst Fe-1. Substituted
benzamides also underwent high-yielding hydrogenation
(entries 3−8), albeit at elevated temperature (130 °C), pressure
(50 bar), and catalyst loading (4 mol %). Benzamides bearing
23
hydrogenation for other amide substrates (but not DMF).
Finally, by decreasing the catalyst loading of Fe-2a to 0.038 mol
and increasing the H pressure to 60 bar, we obtained 1080
%
electron-withdrawing p-F, p-CF , and p-CN substituents
2
3
turnover numbers over 12 h (eq 1).
exhibited the highest reactivity (entries 6−8), while derivatives
6
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a
Table 2. Scope of Formamide Substrates
a
Conditions: 3 mmol of amide, 10 μmol of Fe-2a, 50 μmol of K PO , 2 mL of THF, 20 bar of H , 110 °C, 3 h. Yields are isolated yields of the amine
3
4
2
1
b
1
product. Conversions (based on DMF) and TONs (based on CH OH) were determined by H NMR spectroscopy. Yield determined by H NMR
3
spectroscopy based on CH OH.
3
with electron-donating p-OMe or NMe groups afforded <1%
yield (entry 10 and the Supporting Information). In the case of
consistent with a very recent computational report demonstrat-
2
II
ing similar activation barriers for ester hydrogenation with M -
25,66
p-CN-N,N-diphenylbenzamide (entry 8), both the amide and
PNP catalysts (M = Fe, Ru).
These experimental and
62
the cyano functional groups underwent hydrogenation. Fe-2a
is also compatible with potentially coordinating pyridine
functional groups (entry 9) and catalyzes the hydrogenation
of trifluoromethyl amides under conditions significantly milder
computational results are particularly noteworthy considering
that previous studies have demonstrated orders of magnitude
differences in the kinetic hydricity of first-row transition-metal
67
hydrides versus their second-/third-row counterparts.
22
than those reported with Fe-1 (entry 11). Overall, the
A plausible catalytic cycle for Fe-catalyzed amide hydro-
genation is shown in Scheme 3. This mechanism is similar to
those reported in the literature for carbonyl hydrogenation with
substrate scope, catalyst loading, and TONs obtained with Fe-
33,37
2a rival those of many Ru catalysts.
25
We next sought to compare the rate of amide hydrogenation
related Ru and Fe catalysts. In a catalyst initiation step, the
with Fe-2a to that of its Ru analogue Ru-2a. This comparison
loss of BH from A leads to the active trans-dihydride complex
3
was conducted by monitoring the hydrogenation of DMF via in
B. The BH is presumably captured by a Lewis base in solution
(e.g., solvent, PO4 , etc.). Complex B then transfers a hydride
3
63−65
3−
situ Raman spectroscopy.
As shown in Figure 1, the
complete consumption of DMF required ∼5.5 h with Fe-2a,
while with Ru-2a the amide substrate was fully converted within
and a proton to the amide substrate (step a) to yield a
hemiaminal intermediate and C. Heterolytic cleavage of H by
2
∼
3 h. Comparison of the initial reaction rates shows that the Ru
catalyst is ∼1.7-fold faster than the Fe catalyst. This result is
C regenerates B (step b), while the hemiaminal intermediate
extrudes the amine and concomitantly generates the aldehyde.
6
379
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a
Table 3. Scope of Amide Substrates
a
Conditions unless specified otherwise: 0.25 mmol of amide, 10 μmol of Fe-2a, 50 μmol of K PO , 2 mL of THF, 50 bar of H , 130 °C, 3 h. Yields
3
4
2
1
are isolated yields of the amine product. Conversions (based on amide substrate) and TONs (based on ROH) were determined by H NMR
spectroscopy. Conditions: 0.50 mmol of amide, 10 μmol of Fe-2a, 50 μmol of K PO , 2 mL of THF, 30 bar of H , 110 °C, 3 h. The nitrile
b
c
3
4
2
d
functional group was also hydrogenated. Conditions: 3 mmol of amide, 10 μmol of Fe-2a, 50 μmol of K PO , 2 mL of THF, 20 bar of H , 110 °C, 3
3
4
2
h. Conversion was determined by 19F NMR spectroscopy and yield by H NMR spectroscopy based on 2,2,2-trifluoroethanol.
1
t
Finally, hydrogenation of the aldehyde by B (step c) yields the
primary alcohol and re-forms C. Importantly, an exogeneous
base is not necessary for this cycle to proceed; consistent with
this, our results show that added base is not necessary to
achieve efficient catalysis (Table 1, entry 5). We hypothesize
that the enhanced TONs in the presence of relatively weak
bases such as K PO and NEt are likely due to either base-
ineffectiveness of strong bases (e.g., KO Bu, KHMDS, KOEt;
Table 1, entries 9−11) appears to be a result of their
incompatibility with the substrate, DMF.
6
8
To gain additional mechanistic insights into this trans-
formation, we monitored the reaction progress of the Fe-2a-
catalyzed DMF hydrogenation as a function of H pressure via
Raman spectroscopy. As shown in Figure 2, the reaction
2
3
4
3
promoted catalyst initiation (via sequestration of BH ) and/or
progress curves are nearly identical at 50 and 70 bar of H . In
3
2
the base acting as a proton shuttle during reaction. The
contrast, the reaction is significantly slower at 20 bar of H , and
2
6
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Figure 2. Reaction progress of the hydrogenation of DMF with Fe-2a
Figure 1. Reaction progress of the hydrogenation of DMF with Fe-2a
vs Ru-2a. Conditions: 10.5 mmol of amide, 35 μmol of Fe-2a or Ru-
at 20, 50, and 70 bar of H . Conditions: 10.5 mmol of amide, 35 μmol
2
of Fe-2a, 175 μmol of K PO , 7 mL of THF. The disappearance of
3
4
2
a, 175 μmol of K PO , 7 mL of THF, 70 bar of H . The
−1
3
4
2
DMF was monitored via the Raman peak at 865 cm . Reactions were
conducted in a high-pressure reactor fitted with a Raman probe, and
the temperature was equilibrated to 110 °C (internal temperature)
prior to data collection.
disappearance of DMF was monitored via the Raman peak at 865
−1
cm . Reactions were conducted in a high-pressure reactor fitted with
a Raman probe, and the temperature was equilibrated to 110 °C
(
internal temperature) prior to data collection.
CONCLUSIONS
■
In summary, this article describes the development of an Fe-
catalyzed hydrogenation of unactivated amides to generate
alcohols and amines. Under optimized conditions, this
transformation affords TONs ranging from 25 to 300 and
exhibits a broad scope. Turnover numbers as high as 1000 were
observed for N,N-dimethylformamide hydrogenation. Kinetic
there appears to be an induction period at this lower pressure.
While more detailed studies will be necessary to fully interpret
these data, the preliminary results suggest that either the
turnover-limiting step and/or the initiation rate change as a
function of H pressure.
2
Scheme 3. Proposed Mechanism for the Fe-Catalyzed Hydrogenation of Amides
6
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experiments using in situ Raman spectroscopy demonstrate that
the rate of amide hydrogenation with Fe-2a can approach that
of its noble-metal Ru counterpart. Efforts to elucidate the
mechanistic similarities/differences between the Fe and Ru
catalysts in more detail as well as to design second-generation
Fe catalysts with improved activity are underway in our
laboratory and will be reported in due course.
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ASSOCIATED CONTENT
■
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AUTHOR INFORMATION
■
Corresponding Author
E-mail for M.S.S.: mssanfor@umich.edu.
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■
This work was supported by NSF under the CCI Center for
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Phase II Renewal, CHE-1205189 as well as by the Danish
National Research Foundation through the Carbon Dioxide
Activation Center (CADIAC). N.M.R. thanks Rackham
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1
7,18
(
52) Fe-2b has been demonstrated for ester hydrogenation.
Additionally, a very recent report demonstrated that Fe-2a is also
21
effective for ester hydrogenation.
53) Fe-2a offers the additional advantages that it is straightforward
to synthesize and exhibits high solubility in our reaction solvent
THF).
54) These initial conditions were selected on the basis of our studies
(
(
(
4
6
of DMF hydrogenation with a related Ru pincer catalyst.
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55) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40−73.
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(
t
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59) The use of NaOEt, KO Bu, and KHMDS resulted in poor mass
balance, suggesting incompatibility between these bases and the DMF
substrate.
(
60) Catalyst Fe-2c has been reported for the hydrogenation of
21 23
esters and, recently, a small subset of amides. To confirm the
activity of our samples of Fe-2c, we also performed the hydrogenation
of methyl benzoate (using 1 mol % of Fe-2c and 30 bar of H at 60 °C
2
for 6 h) and benzanilide (using 4 mol % of Fe-2c, 20 mol % of K PO ,
3
4
and 50 bar of H2 at 110 °C for 3 h). In our hands, these
transformations afforded >99% yield (100 turnovers) and 70% yield
(
18 turnovers), respectively.
61) Cabrero-Antonino, J. R.; Alberico, E.; Drexler, H.-J.; Baumann,
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65) Our Raman setup requires a larger reaction volume than the
(
(
5
(
(
(
standard reaction conditions (7 vs 2 mL) in order to submerge the
Raman probe; as such, the concentration of DMF was kept constant
between the two volumes, and all other components were scaled
appropriately to maintain consistent ratios.
(
66) The low reactivity of amides bearing electron donor groups (e.g,
Table 2 entry 4 and Table 3, entry 10) provides preliminary evidence
in support of rate-limiting hydride transfer with catalyst Fe-2a.
(
67) For example, see: Cheng, T.-Y.; Brunschwig, B. S.; Bullock, R.
M. J. Am. Chem. Soc. 1998, 120, 13121−1317.
̌
̌
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a, M.; Drací
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L.; Jansa, P.; Sal
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nsky, M.; Holy, A.; Janeba,
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383
DOI: 10.1021/acscatal.6b01454
ACS Catal. 2016, 6, 6377−6383