Selective Iron-Catalyzed Deaminative Hydrogenation of Amides

Article abstract of DOI:10.1021/acs.organomet.6b00816

The five-coordinate iron(II) hydride complex (^iPrPNP)Fe(H)CO (^iPrPNP = N[CH₂CH₂(PⁱPr₂)]₂) was found to selectively catalyze deaminative hydrogenation of amides to the corresponding amines and primary alcohols. It is one of the most active amide hydrogenation catalysts reported to date, with turnover numbers (TONs) in excess of 1000 observed for multiple substrates and TONs greater than 4000 obtained for activated formanilides. The amide C-N cleavage reactions occur with a preference for electron-withdrawing substituents and with greater activity for formamides compared with acetamides and benzamides. Stoichiometric reactions between (^iPrPNP)Fe(H)CO and formanilide afforded the new iron(II) complex (^iPrPN^HP)Fe(H)CO(N(Ph)HCO) resulting from N-H addition across the Fe-N bond. Complexes of this type were identified as the resting state during catalytic hydrogenation reactions containing secondary amides. Addition of a Lewis acid cocatalyst provided further enhancement of the productivity of catalytic amide hydrogenations.

Full text of DOI:10.1021/acs.organomet.6b00816

Article
pubs.acs.org/Organometallics
Selective Iron-Catalyzed Deaminative Hydrogenation of Amides
Upul Jayarathne,† Yuanyuan Zhang,† Nilay Hazari,‡ and Wesley H. Bernskoetter*,†
†Department of Chemistry, University of Missouri, Columbia, Missouri 65211, United States
‡Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
S
* Supporting Information
ABSTRACT: The five-coordinate iron(II) hydride complex
(iPrPNP)Fe(H)CO (iPrPNP = N[CH2CH2(PiPr2)]2) was found
to selectively catalyze deaminative hydrogenation of amides to
the corresponding amines and primary alcohols. It is one of the
most active amide hydrogenation catalysts reported to date, with
turnover numbers (TONs) in excess of 1000 observed for
multiple substrates and TONs greater than 4000 obtained for
activated formanilides. The amide C−N cleavage reactions occur
with a preference for electron-withdrawing substituents and with greater activity for formamides compared with acetamides and
benzamides. Stoichiometric reactions between (iPrPNP)Fe(H)CO and formanilide afforded the new iron(II) complex
(iPrPNHP)Fe(H)CO(N(Ph)HCO) resulting from N−H addition across the Fe−N bond. Complexes of this type were identified
as the resting state during catalytic hydrogenation reactions containing secondary amides. Addition of a Lewis acid cocatalyst
provided further enhancement of the productivity of catalytic amide hydrogenations.
(TON) of 1000 using a combination of [Ru(η3-C3H5)(Ph2P-
(CH2)2NH2)2]BF4 (A) and 2 equiv of NaBH4 to reduce N,N-
INTRODUCTION
Amides are among the most pervasive functional groups in
■
diphenylacetamide (50 atm, 100 °C, 24 h) (Figure 2).8 In fact,
nearly all of the previously reported ruthenium catalysts for
deaminative hydrogenation require the addition of exogenous
base, with most of the other systems also failing to demonstrate
TONs of >500. The exceptions to this trend are the PNN-
pincer ruthenium catalysts B and C (Figure 3) described by
Milstein9 and Beller10 that do not require a base. Catalyst B
hydrogenates a range of amide substrates, with TONs limited
to ca. 100 (10 atm, 110 °C, 48 h),9 while catalyst C is even
more active, achieving TONs near 500 for multiple amides (30
atm, 120 °C, 18 h).10
naturally occurring molecules.1 These relatively unreactive
carboxylic acid derivatives have diverse roles in chemistry
ranging from the structural backbone in peptide linkages to
small-molecule therapeutic agents.2 Synthetic chemists have
long sought efficient and selective catalytic methods to reduce
amides via hydrogenation as an alternative to contemporary
methods for reduction that rely heavily on waste-generating
stoichiometric reagents.3 Traditionally, efforts to develop amide
hydrogenation catalysts have focused on homogeneous
ruthenium systems, and there are now multiple examples of
catalysts that selectively reduce amides via C−N bond cleavage
(deaminative hydrogenation) or C−O bond cleavage (deoxy-
genative hydrogenation) (Figure 1). Both reduction pathways
While state-of-the-art catalysts for amide hydrogenation are
currently based on ruthenium, developing more active catalysts
using less expensive and toxic metals would greatly enhance the
prospects for the large-scale utilization of deaminative hydro-
genation methods. To date, homogeneous base-metal catalysts
for amide hydrogenation are exceedingly rare.11 Milstein and
co-workers recently reported the first such species, the pyridyl-
based iron pincer complex [C5H3N-2,6-(CH2PiPr2)2]Fe(H)Br-
(CO) (D), which, when combined with exogenous base,
hydrogenated N-substituted 2,2,2-trifluoroacetamides to give
the corresponding amines and trifluoroethanol, in some cases
with high conversions (99%) and TONs of up to 50 (60 atm,
140 °C, 12−36 h) (Figure 4).11a Unfortunately, the hydro-
genation was limited to only CF3-activated amides, and no
reaction was observed with more common substrates such as
N-phenylacetamide and N-phenylbenzamide. Our own labo-
ratories, along with other investigators, have developed related
Figure 1. Divergent selectivity for the hydrogenation of amides.
are potentially useful, with the difference in selectivity related to
the mechanism through which a common intermediate
hemiaminal species reacts.4 While several highly active
heterogeneous catalysts for amide hydrogenation have been
recently reported, their poor selectivity, including reduction of
ancillary aromatic rings,5 has led to increased research effort to
develop improved homogeneous catalysts.6,7 Bergens and co-
workers reported one of the most active catalytic systems for
deaminative hydrogenation, achieving a turnover number
Received: October 26, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.6b00816
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Figure 2. Ruthenium-catalyzed hydrogenation of N,N-diphenylacetamide described by Bergens and co-workers.8
Figure 5. Initial studies of amide hydrogenation catalyzed by 1.
catalysts,{HN[CH2CH2(PR2)]2}Fe(H)CO(η1-BH4) (R = Et,
Cy), were reported by Langer and Sanford, respectively.11b,c As
part of a study of ester hydrogenation, the Et2P-substituted
pincer complex was reported to hydrogenate a small group of
amides, with a comparable TON of 23 for N-phenylbenzamide
(50 atm, 70 °C, 24 h). Oddly, the scope and general activity of
this precatalyst are considerably weaker than observed here,
possibly as a result of small differences in the ancillary ligand or
precatalyst structure (vide infra).11b The Cy2P-substituted
analogue exhibited a comparable TON of 25 for N-phenyl-
benzamide (50 atm, 130 °C, 3 h) but was successful at
hydrogenating a broader range of 2° and 3° amides than the
Et2P-substituted congener, with TONs of 25−300 commonly
observed (a notable TON of 1080 was achieved for
dimethylformamide). However, in catalysis using {HN-
[CH2CH2(PCy2)]2}Fe(H)CO(η1-BH4) an exogenous base
was required to obtain the best performance.
Given the high preliminary TONs in the reduction of 4-
formylmorpholine and formanilide using 1, we employed these
amides to screen different conditions for hydrogenation.
Altering the reaction conditions for the hydrogenation of 4-
formylmorpholine in Figure 5 from 60 atm H2 to 30 atm
lowered the TON to 1090. However, this drop in activity could
be recovered by raising the temperature to 100 °C, affording a
TON of >1390 (∼99% conv.) at 30 atm. Periodic sampling of
this reaction indicated complete conversion was achieved after
only 4 h, providing a new set of standard reaction conditions of
30 atm H2 at 100 °C over 4 h. Following this optimization, the
influence of the solvent was examined using a 1.25 μmol (0.018
mol %, TONmax = 5600) catalyst loading (Table 1). In these
reactions, solid formanilide was preferred over liquid 4-
formylmorpholine as the substrate because of the relative
ease of purifying, drying, and handling the multigram quantities
required to complete these catalytic trials. Aside from a notable
Figure 3. Ruthenium PNN-pincer catalysts for deaminative amide
hydrogenation.
pincer-supported iron catalysts for a variety of hydrogenation
and dehydrogenation reactions.12 The five-coordinate iron(II)
complex (RPNP)Fe(H)CO (RPNP = N[CH2CH2(PR2)]2, R =
iPr, Cy) has proven particularly effective at hydrogenating
substrates such as esters, olefins, nitrogen heterocycles, and
CO2.13 Herein we report the application of [(RPNP)Fe]
catalysts in the selective base-free hydrogenation of a range of
secondary and tertiary amides. The catalytic TONs for many of
these amide substrates surpass even those of precious-metal
catalysts. From a fundamental perspective, the addition of
Lewis acid salts and small amounts of a secondary amide result
in significantly enhanced activity for challenging substrates.
RESULTS AND DISCUSSION
■
Our investigation into iron-catalyzed amide hydrogenation
began with experiments using (iPrPNP)Fe(H)CO (1) as the
catalyst for the reduction of formanilide, N-phenylbenzamide,
and 4-formylmorpholine (Figure 5). Despite the use of
relatively mild conditions (60 atm, 60 °C, 16 h), the initial
catalytic results were highly promising. Catalyst 1 hydrogenated
both formamide substrates with TONs comparable to or
slightly higher than those of the most active ruthenium catalysts
reported to date and with essentially complete selectivity for
methanol and the corresponding amines.14 These observations
suggested that unprecedented catalytic activity may be possible
with further optimization and mechanistic insight. Even the
small TON of 20 for N-phenylbenzamide was noteworthy
given the inability of Milstein’s iron catalyst D to reduce this
substrate. During the course of the investigations described
herein, two related iron hydridoborohydride carbonyl pre-
Figure 4. First iron-catalyzed hydrogenation of trifluoroacetamides reported by Milstein and co-workers.
B
DOI: 10.1021/acs.organomet.6b00816
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
these tests, a serendipitous observation was made regarding
tertiary formamide substrates. For example, when N-methyl-
formanilide was used as the substrate in the presence of
formanilide, both compounds were completely hydrogenated,
equivalent to a TON of 700 for each amide; however,
independent hydrogenation of N-methylformanilide afforded
vanishingly small conversion (Table 2, entry 6). The origin of
this enhancement of deaminative hydrogenation was probed by
performing separate catalytic trials of N-methylformanilide
hydrogenation with 20 equiv (with respect to 1) of formanilide,
aniline, and methanol. Hydrogenations containing aniline and/
or methanol (the products of formanilide hydrogenation)
afforded TONs of less than 350 (Table S3), suggesting that
formanilide itself improved the conversion. Indeed, addition of
20 equiv (with respect to 1) of formanilide to N-
methylformanilide hydrogenation (Figure 6) increased the
TON from 60 to 1300 under the conditions in Table 2. Similar
activity enhancements were also observed when formanilide
was spiked into other tertiary amides (vide infra).
Table 1. Solvent Screening for Formanilide Hydrogenation
Catalyzed by 1
a
b
solvent
TON
tetrahydrofuran
1,4-dioxane
acetonitrile
ethyl acetate
toluene
3240
2300
<10
2440
2840
a
Reaction conditions: 30 atm H2 (450 psi), 1.25 μmol of 1 (0.018 mol
%), and 7 mmol of formanilide in 5 mL of solvent at 100 °C for 4 h.
b
Determined by NMR spectroscopic analysis of the product amine
and residual starting material. Each entry is the average of two or more
trials.
inactivity in acetonitrile, probably due to catalyst decom-
position, the catalyst performed well in several polar solvents,
with THF providing the highest TON of 3240. Our system is
also compatible with nonpolar solvents such as toluene,
although many amide substrates have limited solubility in
these media.
A series of NMR experiments were performed to examine
the mechanism of formanilide enhancement of amide hydro-
genation. First, the stoichiometric treatment of 1 with
formanilide (eq 1) resulted in a bleaching of the dark-red
The substrate scope of amide hydrogenation catalyzed by 1
was explored using conditions based on our reaction
optimization (Table 2). A series of amides were hydrogenated
under 30 atm H2 at 100 °C over 4 h in THF with a 5.0 μmol
loading of 1 (0.070 mol %; TONmax = 1400). Those substrates
that achieved >90% conversion under these conditions were
also tested with a 1.25 μmol (0.018 mol %; TONmax = 5600)
loading of 1 to better ascertain the limits of the activity. The
results offer several insights into trends associated with iron-
catalyzed deaminative hydrogenation. Entries 1−5 indicate a
moderate preference for the hydrogenation of amides bearing
electron-withdrawing N-substituents, with the p-CF3-substi-
tuted formanilide affording ca. 2500 additional turnovers
compared with the p-OMe-substituted congener under low-
catalyst-loading conditions. Notably, at higher catalyst loading
all of the studied formanilides were fully hydrogenated to the
corresponding amines and alcohols with essentially complete
selectivity. Consistent with the electronic activation of the
formanilides, secondary formamides were more reactive than
the related tertiary formamides (entries 3, 6, and 7), with those
bearing aryl groups achieving higher TONs than alkylated
formamides. 4-Formylmorpholine (entry 8) is a notable
exception to this trend, although the presence of a cyclic
substituent differentiates it from other substrates. The general
preference for deaminative hydrogenation of electron-poor
substrates is also evident in the variation in catalytic
performance as the amide carbonyl substituent was changed
(entries 3 and 9−11). Comparison of the TONs for the CH3-
and CF3-substituted carbonyl (entries 9 and 11) with the H-
substituted formamide (entry 3) also suggests that steric factors
play an important role in hydrogenation. Both of the larger
amides are more challenging substrates, despite providing
electronically different influences.
solution to yellow and the observation of two new resonances
in the 31P NMR spectrum. These singlet peaks appeared at
96.85 and 91.14 ppm in a 1:3 ratio, suggesting two isomeric
1
products. The corresponding H NMR spectrum also held
several resonances of interest, including a pair of triplet Fe−H
signals at −22.82 ppm (major) and −25.98 ppm (minor). The
downfield region of the NMR spectrum revealed four
resonances ranging from 8 to 11 ppm assigned to the
(iPrPNHP) N−H and formamide C−H moieties with the aid
of 1H−13C HMQC NMR experiments. These data are
consistent with formation of an iron(II) formanilide hydride
carbonyl complex, (iPrPNHP)Fe(NPhCHO)CO(H) (2), pro-
duced by formal addition of the amide N−H across the Fe−N
bond. The presence of two isomeric products is likely due to
the formation of conformational isomers of the formanilide as a
result of hindered rotation about the C−N bond. Isomers
varying through different coordination sites of the formanilide,
hydride, and CO ligands are also possible, though less likely
given the need to partially dissociate the iPrPNHP ligand in
order to interchange these positions. Assignment of the
formanilide complex was confirmed by single-crystal X-ray
diffraction of a sample containing one isomer of 2 (Figure 7).
The molecular structure of 2 exhibits a slightly distorted
octahedral geometry about the iron center with the Fe(1)−
N(2) formamide linkage lying opposite the Fe(1)−H(1) bond.
The bound amide appears to be hydrogen-bonded to the pincer
N−H bond, with a short interaction distance of 1.84 Å between
O(2) and H(2). To further elucidate the details of the amide
hydrogenation reaction, a pair of NMR-tube-scale catalytic
reactions were monitored in situ. Two J. Young NMR tubes
As noted earlier, the low loadings of 1 required that amide
substrates be purified and dried prior to use in catalytic
reactions. As a practical test for purity, substrates were routinely
mixed with formanilide (ca 700 equiv of each with respect to 1)
and hydrogenated under the conditions used in Table 2. The
hypothesis was that impurities in the new substrates would
become evident from a reduction in the conversion of
formanilide, which is otherwise fully hydrogenated to aniline
and methanol under these conditions. During the course of
C
DOI: 10.1021/acs.organomet.6b00816
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
a
Table 2. Deaminative Hydrogenation of Amides Catalyzed by 1
a
Reaction conditions: 30 atm H2 (∼450 psi), 5.0−1.25 μmol of 1 (0.07−0.018 mol %), and 7 mmol of amide in 5 mL of THF at 100 °C for 4 h.
Determined by NMR and GC analyses of the product amine or alcohol (in the case of highly volatile product amines) as well as residual starting
b
material. Each entry is the average of two or more trials.
were charged with a benzene-d6 solution of 1 and 4 equiv of N-
methylformanilide. No apparent reaction between the tertiary
amide and the five-coordinate iron compound was detected at
ambient temperature over 1 h (Figures S5 and S6). Then
D
DOI: 10.1021/acs.organomet.6b00816
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Figure 6. Influence of 2° amide addition on N-methylformanilide hydrogenation.
elucidate the influences of formanilide on the catalytic
deaminative hydrogenation.
The enhancement of tertiary amide hydrogenation upon
addition of formanilide motivated a systematic examination of
additive influences, with our focus drawn to dimethylforma-
mide (DMF). DMF was the only formamide substrate from our
initial screening (Table 2) that failed to produce any turnover.
This is presumably due to the electron-donating nature of the
methyl substituents on nitrogen. In addition, DMF hydro-
genation is a prominent component in the net hydrogenation
of CO2 to methanol with related ruthenium catalysts.7e Prior
work in our laboratories has shown significant enhancements in
hydrogenation reactions catalyzed by 1 in the presence of Lewis
acidic salts, such as lithium triflate (LiOTf), and thus, a set of
comparative catalytic experiments on DMF hydrogenation were
conducted to ascertain the effect of Lewis acid here (Table 3).
Figure 7. Molecular structure of 2 with 30% ellipsoids. Most of the
hydrogen atoms have been removed for clarity. Selected bond lengths
(Å) and angles (deg): Fe(1)−P(1) 2.2190(3), Fe(1)−P(2) 2.2042(3),
Fe(1)−N(1) 2.0855(8), Fe(1)−C(1) 1.7209(11), Fe(1)−N(2)
2.1287(9), P(1)−Fe(1)−P(2) 159.677(12), N(1)−Fe(1)−C(1)
171.851(4).
Table 3. Influence of LiOTf and Formanilide on the 1-
Catalyzed Hydrogenation of DMF
a
formanilide (2 equiv with respect to 1) was introduced into one
of the tubes before both samples were exposed to 4 atm H2. 31P
additive
b
1
entry
LiOTf
HCON(H)Ph
TON
and H NMR spectra obtained immediately after H2 addition
displayed resonances for different iron species in each sample.
The NMR tube containing formanilide exhibited clean
formation of 2, while the sample without formanilide produced
two isomers of the previously reported iron(II) dihydride
carbonyl complex (iPrPNHP)FeH2CO (3). Heating the samples
at 50 °C for 24 h resulted in incomplete catalytic hydrogenation
of N-methylformanilide to methanol and N-methylaniline in
both reactions, though the identity of the primary organo-
metallic species remained unchanged. This suggests that the
resting states are different in the two catalytic systems and that
the primary influence of formanilide is to change the resting
state (Figure 8). It is feasible that formation of the relatively
stable complex 2 protects the iron from deleterious side
reactions during preparation of the catalytic experiment.
Additional mechanistic investigations will be required to fully
1
2
3
4
−
−
−
50
220
190
340
0.1 mmol
−
0.1 mmol
0.1 mmol
0.1 mmol
a
Reaction conditions: 60 atm H2 (∼900 psi), 5.0 μmol of 1 (0.07 mol
%), and 7 mmol of DMF in 5 mL of THF at 120 °C for 16 h.
Determined by NMR and GC-FID analyses of the product alcohol
and residual starting material. Each entry is the average of two or more
trials.
b
DMF hydrogenation experiments in the presence of LiOTf
resulted in a significant enhancement of the TON from 50 with
no additive (entry 1) to 220 with a 0.1 mmol (1.4 mol %)
loading of Lewis acid (entry 2). This increase in activity is
comparable to the enhancement obtained by addition of an
Figure 8. Alteration of the catalyst resting state by formanilide.
E
DOI: 10.1021/acs.organomet.6b00816
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
equal amount of formanilide (entry 3), which afforded a TON
of 190. A combination of both promotors in an equal molar
ratio produced a nearly additive enhancement effect, achieving
a TON of 340 (entry 4).
The beneficial influence of both formanilide and LiOTf on
the hydrogenation of DMF motivated a brief re-examination of
some challenging substrates from Table 2. A selection of amide
substrates that achieved low TONs under the prior conditions
were evaluated for deaminative hydrogenation by 1 in the
presence of both promoters (Table 4). The enhancement of 4-
defined iron system, and with TONs in excess of 1000 for
several substrates, it is superior in activity to most reported
ruthenium catalysts. The substrate scope of deaminative amide
hydrogenation shows a clear preference for electron-poor
amides, possibly originating from an enhanced electrophilicity
at the carbonyl and relatively facile delivery of hydride from the
iron. Likewise, the substrate scope reveals a preference for
sterically unencumbered amides, with even small acetamides
and benzamides exhibiting reduced activities compared with the
corresponding formamides. Stoichiometric and in situ catalytic
NMR studies revealed a difference between iron-catalyzed
hydrogenation of secondary and tertiary amides. Secondary
amides, and formanilide in particular, rapidly add across the
Fe−N bond of 1 to generate the relatively stable Fe−
formanilide complex 2. Complex 2 appears to be the catalytic
resting state for hydrogenation reactions conducted in the
presence of secondary amides (even when only present in small
amounts), while the previously reported Fe−dihydride complex
3 was the primary iron species observed in the hydrogenation
of pure tertiary amides. The substantial enhancements in the
hydrogenation of tertiary amides in the presence of a small
amount of secondary amide likely derive from this change in
resting states. However, a more complete mechanistic study,
including computational and experimental probes, will be
required to fully elucidate the origins of the secondary amide
effect as well as enhancements observed by the addition of
LiOTf. These investigations as well as further application of the
iron-catalyzed methodology are among the foci of our ongoing
current work.
Table 4. Hydrogenation of Selected Amides under the
a
Modified Reaction Conditions
EXPERIMENTAL SECTION
■
General Considerations. All manipulations were carried out using
standard vacuum, Schlenk, cannula, or glovebox techniques. Hydrogen
was purchased from Airgas and used as received. Catalyst 1 was
prepared as previously described.12h Amide substrates that were not
commercially available were prepared using a previously reported
procedure.15 All other chemicals were purchased from Aldrich, Fisher,
VWR, Strem, or Cambridge Isotope Laboratories. Amide substrates
were dried and purified by a combination of sublimation and
recrystallization from anhydrous ethereal solvents. All other non-
volatile solids were dried under vacuum at 50 °C overnight. Solvents
were dried and deoxygenated using literature procedures.16 1H, 13C,
and 31P NMR spectra were recorded on Bruker 300 MHz DRX, 500
MHz DRX, or 600 MHz spectrometers at ambient temperature, unless
otherwise noted. 1H and 13C chemical shifts are referenced to residual
solvent signals; 31P chemical shifts are referenced to an external
standard of H3PO4. Probe temperatures were calibrated using ethylene
glycol and methanol as previously described.17 High-pressure catalytic
hydrogenation reactions were performed using a Parr 5500 series
compact reactor with glass insert.
a
Reaction conditions: 60 atm H2 (900 psi), 5 μmol of 1 (0.070 mol
%), and 7 mmol of DMF in 5 mL of THF at 120 °C for 16 h.
b
Determined by GC analysis of the product amine as well as the
residual starting material. Each entry is the average of two or more
trials. The reaction was conducted with 1.25 μmol of 1 (0.018 mol
%).
c
formylmorpholine was also measured for comparative purposes.
Addition of 20 equiv of LiOTf and fomanilide (with respect to
1), along with increasing the temperature and the pressure of
H2, increased the TON for acetanilide and benzanilide from 50
and 130 (Table 2, entries 9 and 10) to 200 and 190,
respectively (Table 4, entries 1 and 2). However, the addition
of cocatalysts was still unable to produce effective reduction of
N-methylbenzamide (Table 4, entry 4), likely because of the
combination of the sterically demanding arene substituent on
the carbonyl and the electron-donating N-methyl group. Some
enhancement in TON was observed for the already activated
substrate 4-formylmorpholine, for which the TON increased
from 2000 to 3010 (Table 4, entry 5) under the modified
reaction conditions.
Synthesis of (iPrPNHP)Fe(NPhCHO)CO(H) (2). A 20 mL
scintillation vial was charged with a sample of 1 (0.050 g, 0.128
mmol) and approximately 5 mL of THF. While stirring, a formanilide
solution (0.141 mL of 1 M solution in THF) was added, immediately
producing a color change from reddish purple to yellow. This reaction
mixture was stirred for 4 h, and then the volatiles were removed under
reduced pressure to afford an oily residue. The residue was extracted
with pentane (3 mL × 3), filtered through Celite, and evaporated
under reduced pressure. The product was recrystallized from minimal
pentane at −35 °C overnight to yield 2 (0.041 g, 63%) as a yellow
crystalline solid. Crystals suitable for X-ray diffraction were grown by
slow evaporation of a pentane solution. Evidence for the purity of 2 is
provided by the spectroscopic data in the Supporting Information. 1H
NMR (C6D6) (two isomers observed): major isomer: δ 10.75 (s, 1H,
N-H), 8.98 (s, 1H, HCO), 7.43 (d, 2H, PhH), 7.25 (t, 2H, PhH) 6.96
(t, 1H, PhH), 2.85 (m, 2H, CH2), 2.26 (m, 2H, CH2), 1.96 (m, 2H,
CONCLUDING REMARKS
■
The base-free catalytic reduction of amides to amines and
primary alcohols by 1 is one of the first observed using a well-
F
DOI: 10.1021/acs.organomet.6b00816
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
CH2), 1.70 (m, 2H, CH2), (m, 2H, CH2), 0.88−1.22 (PiPr2), −22.82
(t, J = 57 Hz, Fe-H); minor isomer: 10.35 (s, 1H, N-H), 8.81 (s, 1H,
HCO), (PhH, CH2, PiPr2 peaks all overlap with those of the major
isomer, as confirmed by HMQC NMR spectra), −25.98 (t, J = 51 Hz,
Fe-H). 31P{1H} NMR (C6D6): minor isomer: δ 96.85 (d, J = 45 Hz);
major isomer: 91.14 (t, J = 18 Hz). Partial 13C{1H} from HMQC for
both isomers: δ 177.08 (HC(O)), 128.49 (Ar), 127.72 (Ar),
122.71(Ar), 53.93, 53.39, 29.43, 28.94, 26.13, 21.11, 24.55, 19.97,
19.74, 19.48 (CH2 and PiPr2).
General Method for Catalytic Amide Hydrogenation
Studies. Inside a glovebox, a glass reactor liner (50 mL) was charged
with the amide (7 mmol) and THF to a total volume of 5 mL. Then a
solution of 1 (either 5.0 or 1.25 μmol) in THF was added to this
mixture via microsyringe. If LiOTf, formanilide, or other additives
were tested, they were added at this time. Then the Parr reactor was
sealed and removed from the glovebox. The reactor was pressurized
with commercial-grade H2 at ambient temperature (∼450 or 900 psi)
and then heated (100 or 120 °C in typical experiments) with
mechanical stirring. After the allotted time (4−16 h), the reactor was
cooled by submersion in an ice bath, and the H2 was slowly vented.
The product solution was then analyzed by 1H NMR spectroscopy and
GC-MS or GC-FID using mesitylene as a standard.
Brosinski, S.; Leitner, W.; Cole-Hamilton, D. J. Chem. Commun. 2012,
48, 12249−12262. (c) Coetzee, J.; Dodds, D. L.; Klankermayer, J.;
Brosinski, S.; Leitner, W.; Slawin, A. M. Z.; Cole- Hamilton, D. J.
Chem. - Eur. J. 2013, 19, 11039−11050. (d) vom Stein, T.; Meuresch,
M.; Limper, D.; Schmitz, M.; Holscher, M.; Coetzee, J.; Cole-
Hamilton, D. J.; Klankermayer, J.; Leitner, W. J. Am. Chem. Soc. 2014,
136, 13217−13225. (e) Yuan, M.-L.; Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L.
ACS Catal. 2016, 6, 3665−3669.
(7) For examples of deaminative hydrogenation, see these and
subsequent references: (a) Ito, M.; Ootsuka, T.; Watari, R.; Shiibashi,
A.; Himizu, A.; Ikariya, T. J. Am. Chem. Soc. 2011, 133, 4240−4242.
(b) John, J. M.; Bergens, S. H. Angew. Chem., Int. Ed. 2011, 50,
10377−10380. (c) Miura, T.; Held, I. E.; Oishi, S.; Naruto, M.; Saito,
S. Tetrahedron Lett. 2013, 54, 2674−2678. (d) Kita, Y.; Higuchi, T.;
Mashima, K. Chem. Commun. 2014, 50, 11211−11213. (e) Rezayee, N.
M.; Huff, C. A.; Sanford, M. S. J. Am. Chem. Soc. 2015, 137, 1028−
1031. (f) Zhang, L.; Han, Z.; Zhao, X.; Wang, Z.; Ding, K. Angew.
Chem., Int. Ed. 2015, 54, 6186−6189.
(8) John, J. M.; Loorthuraja, R.; Antoniuk, E.; Bergens, S. H. Catal.
Sci. Technol. 2015, 5, 1181−1186.
(9) Balaraman, E.; Gnanaprakasam, B.; Shimon, L. J. W.; Milstein, D.
J. Am. Chem. Soc. 2010, 132, 16756−16758.
(10) Cabrero-Antonino, J. R.; Alberico, E.; Drexler, H.-J.; Baumann,
W.; Junge, K.; Junge, H.; Beller, M. ACS Catal. 2016, 6, 47−54.
(11) (a) Garg, J. A.; Chakraborty, S.; Ben-David, Y.; Milstein, D.
Chem. Commun. 2016, 52, 5285−5288. (b) Schneck, F.; Assmann, M.;
Balmer, M.; Harms, K.; Langer, R. Organometallics 2016, 35, 1931−
1943. (c) Rezayee, N. M.; Samblanet, D. C.; Sanford, M. S. ACS Catal.
2016, 6, 6377−6383.
(12) (a) Langer, R.; Diskin-Posner, Y.; Leitus, G.; Shimon, L. J. W.;
Ben-David, Y.; Milstein, D. Angew. Chem., Int. Ed. 2011, 50, 9948−
9952. (b) Elangovan, S.; Wendt, B.; Topf, C.; Bachmann, S.; Scalone,
M.; Spannenberg, A.; Jiao, H.; Baumann, W.; Junge, K.; Beller, M. Adv.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00816.
■
S
Crystallographic data for 2 (CIF)
Additional experimental data and selected NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: bernskoetterwh@missouri.edu.
Notes
Synth. Catal. 2016, 358, 820−825. (c) Gluer, A.; Forster, M.; Celinski,
̈
̈
■
V. R.; Schmedt auf der Guenne, J.; Holthausen, M. C.; Schneider, S.
ACS Catal. 2015, 5, 7214−7217. (d) Sharninghausen, L. S.; Mercado,
B. Q.; Crabtree, R. H.; Hazari, N. Chem. Commun. 2015, 51, 16201−
16204. (e) Bielinski, E. A.; Forster, M.; Zhang, Y.; Bernskoetter, W.
̈
The authors declare no competing financial interest.
H.; Hazari, N.; Holthausen, M. C. ACS Catal. 2015, 5, 2404−2415.
(f) Fairweather, N. T.; Gibson, M. S.; Guan, H. Organometallics 2015,
34, 335−339. (g) Bornschein, C.; Werkmeister, S.; Wendt, B.; Jiao, H.;
Alberico, E.; Baumann, W.; Junge, H.; Junge, K.; Beller, M. Nat.
Commun. 2014, 5, 4111. (h) Bielinski, E. A.; Lagaditis, P. O.; Zhang,
ACKNOWLEDGMENTS
■
The Curators of the University of Missouri are gratefully
acknowledged for support of this work. N.H. and W.H.B are
Fellows of the Alfred P. Sloan Foundation.
Y.; Mercado, B. Q.; Wurtele, C.; Bernskoetter, W. H.; Hazari, N.;
̈
Schneider, S. J. Am. Chem. Soc. 2014, 136, 10234−10237.
(i) Werkmeister, S.; Junge, K.; Wendt, B.; Alberico, E.; Jiao, H.;
Baumann, W.; Junge, H.; Gallou, F.; Beller, M. Angew. Chem., Int. Ed.
2014, 53, 8722−8726. (j) Chakraborty, S.; Dai, H.; Bhattacharya, P.;
Fairweather, N. T.; Gibson, M. S.; Krause, J. A.; Guan, H. J. Am. Chem.
Soc. 2014, 136, 7869−7872. (k) Lagaditis, P. O.; Sues, P. E.;
Sonnenberg, J. F.; Wan, K. Y.; Lough, A. J.; Morris, R. H. J. Am. Chem.
Soc. 2014, 136, 1367−1380.
(13) (a) Xu, R.; Chakraborty, S.; Bellows, S. M.; Yuan, H.; Cundari,
T. R.; Jones, W. D. ACS Catal. 2016, 6, 2127−2135. (b) Zhang, Y.;
MacIntosh, A.; Wong, J. L.; Bielinski, E. A.; Williard, P. G.; Mercado,
B. Q.; Hazari, N.; Bernskoetter, W. H. Chem. Sci. 2015, 6, 4291−4299.
(c) Bonitatibus, P. J.; Chakraborty, S.; Doherty, M. D.; Siclovan, O.;
Jones, W. D.; Soloveichik, G. L. Proc. Natl. Acad. Sci. U. S. A. 2015,
112, 1687−1692. (d) Chakraborty, S.; Lagaditis, P. O.; Forster, M.;
Bielinski, E. A.; Hazari, N.; Holthausen, M. C.; Jones, W. D.;
Schneider, S. ACS Catal. 2014, 4, 3994−4003. (e) Chakraborty, S.;
Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2014, 136, 8564−
8567.
REFERENCES
■
(1) Arthur, G. The Amide Linkage: Selected Structural Aspects in
Chemistry, Biochemistry, and Materials Science; Wiley-Interscience:
Hoboken, NJ, 2000.
(2) (a) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G.
R.; Leazer, J. L., Jr.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman,
B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411−420.
Wieland, T.; Bodanszky, M. The World of Peptides: A Brief History of
Peptide Chemistry; Springer: Berlin, 1991.
(3) Smith, A. M.; Whyman, R. Chem. Rev. 2014, 114, 5477−5510.
(4) (a) Cantillo, D. Eur. J. Inorg. Chem. 2011, 2011, 3008−3013.
(b) Li, H.; Hall, M. B. ACS Catal. 2015, 5, 1895−1913.
(5) (a) Krackl, S.; Someya, C. I.; Enthaler, S. Chem. - Eur. J. 2012, 18,
15267−15271. (b) Beamson, G.; Papworth, A. J.; Philipps, C.; Smith,
A. M.; Whyman, R. J. Catal. 2010, 269, 93−102. (c) Burch, R.; Paun,
C.; Cao, M.; Crawford, P.; Goodrich, P.; Hardacre, C.; Hu, P.;
McLaughlin, L.; Sa, J.; Thompson, J. M. J. Catal. 2011, 283, 89−97.
(d) Stein, M.; Breit, B. Angew. Chem., Int. Ed. 2013, 52, 2231−2234.
(e) Coetzee, J.; Manyar, H. G.; Hardacre, C.; Cole-Hamilton, D. J.
ChemCatChem 2013, 5, 2843−2847.
(14) No other organic products, except for residual starting material,
were observed by NMR spectroscopy and GC.
(15) Shekhar, A. C.; Kumar, A. R.; Sathaiah, G.; Paul, V. L.; Sridhar,
M.; Rao, P. S. Tetrahedron Lett. 2009, 50, 7099−7101. (b) Kim, J. G.;
Jang, D. O. Tetrahedron Lett. 2010, 51, 683−685. (c) Ohtaka, J.;
(6) For examples of deoxygenative hydrogenation, see: (a) Nunez
Magro, A. A.; Eastham, G. R.; Cole-Hamilton, D. J. Chem. Commun.
2007, 3154−3156. (b) Dodds, D. L.; Coetzee, J.; Klankermayer, J.;
́
̃
G
DOI: 10.1021/acs.organomet.6b00816
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Sakamoto, T.; Kikugawa, Y. Tetrahedron Lett. 2009, 50, 1681−1683.
(d) Ghosh, S.; Das, J. Org. Chem. Int. 2010, 2010, 743186.
(16) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518−1520.
(17) Sandstrom, J. Dynamic NMR Spectroscopy; Academic Press: New
̈
York, 1982.
H
DOI: 10.1021/acs.organomet.6b00816
Organometallics XXXX, XXX, XXX−XXX