Iron-Catalyzed Amide Formation from the Dehydrogenative Coupling of Alcohols and Secondary Amines

Article abstract of DOI:10.1021/acs.organomet.7b00258

The five-coordinate iron(II) hydride complex (^iPrPNP)Fe(H)(CO) (^iPrPNP = N[CH₂CH₂(PⁱPr₂)]₂) selectively catalyzes the dehydrogenative intermolecular coupling of alcohols and secondary amines to form tertiary amides. This is the most productive base-metal catalyst for dehydrogenative amidation reported to date, in some cases achieving up to 600 turnovers. The catalyst works well for sterically undemanding amines and alcohols or cyclic substrates and is particularly effective in the synthesis of formamides from methanol. However, the catalyst performance declines rapidly with the incorporation of large substituents on the amine or alcohol substrate. Variable-temperature NMR spectroscopic studies suggest that the catalyst resting state is an off-cycle iron(II) methoxide species, (^iPrPN(H)P)Fe(H)(OCH₃)(CO), resulting from addition of methanol across the Fe-N bond of (^iPrPNP)Fe(H)(CO). This reversibly formed iron(II) methoxide complex is favored at mild temperatures but eliminates methanol upon heating.

Full text of DOI:10.1021/acs.organomet.7b00258

Article
pubs.acs.org/Organometallics
Iron-Catalyzed Amide Formation from the Dehydrogenative
Coupling of Alcohols and Secondary Amines
Elizabeth M. Lane,† Katherine B. Uttley,‡ Nilay Hazari,§ and Wesley Bernskoetter*,‡
†Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States
‡Department of Chemistry, The University of Missouri, Columbia, Missouri 65211, United States
§Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States
S
* Supporting Information
ABSTRACT: The five-coordinate iron(II) hydride complex
(iPrPNP)Fe(H)(CO) (iPrPNP = N[CH2CH2(PiPr2)]2) selec-
tively catalyzes the dehydrogenative intermolecular coupling of
alcohols and secondary amines to form tertiary amides. This is
the most productive base-metal catalyst for dehydrogenative
amidation reported to date, in some cases achieving up to 600
turnovers. The catalyst works well for sterically undemanding amines and alcohols or cyclic substrates and is particularly effective
in the synthesis of formamides from methanol. However, the catalyst performance declines rapidly with the incorporation of large
substituents on the amine or alcohol substrate. Variable-temperature NMR spectroscopic studies suggest that the catalyst resting
state is an off-cycle iron(II) methoxide species, (iPrPN(H)P)Fe(H)(OCH3)(CO), resulting from addition of methanol across the
Fe−N bond of (iPrPNP)Fe(H)(CO). This reversibly formed iron(II) methoxide complex is favored at mild temperatures but
eliminates methanol upon heating.
combination of these factors. Notably, most existing catalysts
perform best with primary amine substrates, with only a few
ruthenium catalysts demonstrating any compatibility with
secondary amine substrates.16,17,19,21,23−25,27 To date, only
two of these ruthenium catalysts have achieved TONs greater
than 25 for the formation of tertiary amides under base-free
and/or hydrogen-acceptor-free conditions (Figure 1).21,24
Furthermore, the development of promoters incorporating
cheaper, less toxic metals is lacking, as only two base-metal
catalysts (one copper and one manganese) have been described
for this dehydrogenative amidation.29,30 While these recent
studies demonstrate some promise of base-metal-mediated
coupling of amines and alcohols, both exhibit limited tertiary
amide production (TONs < 50). Herein we report the ability of
the five-coordinate iron(II) complex (iPrPNP)Fe(H)(CO) (1;
iPrPNP = N[CH2CH2(PiPr2)]2) to catalyze the dehydrogen-
ation of alcohols in the presence of secondary amines to
selectively produce amides in the absence of hydrogen
acceptors or base promoters (Figure 1). Complex 1 is the
most productive base-metal catalyst yet developed for
intermolecular dehydrogenative amide synthesis and gives
TONs that exceed those previously described for base or
precious metals with respect to tertiary amide formation.31
INTRODUCTION
■
Amides are key functional groups in organic synthesis,
biochemistry, and pharmaceuticals.1 For example, it is
estimated that approximately 25% of drug molecules contain
amide moieties.2 Current methods for large-scale amide
synthesis typically involve the reaction of carboxylic acids or
more commonly their activated derivatives (such as acid
chlorides, acid anhydrides, and acyl azides)3−5 with stoichio-
metric amounts of amines, along with additional inorganic or
organic promoters. As a result, these procedures are not atom
efficient, generate considerable chemical waste, and use
relatively expensive starting materials.1 The dehydrogenative
coupling of alcohols and amines to form amides (with
dihydrogen as the only byproduct; Scheme 1) offers a more
direct and environmentally benign alternative to obtaining
these materials. Although coinage metals such as silver6 and
gold7,8 have demonstrated some effectiveness as heterogeneous
catalysts for dehydrogenative amide synthesis, these systems
normally require high catalyst loadings, harsh reaction
conditions, and long reaction times or have limited substrate
scopes. Homogenous transition-metal catalysts incorporating
rhenium,9 rhodium,10 and (most extensively) ruthenium have
shown greater activity.11−28 The most prominent example, a
ruthenium-pincer catalyst reported in 2007 by Milstein and co-
workers, achieved turnover numbers (TONs) of nearly 1000
for the dehydrogenative coupling of primary amines with
sterically accessible alcohols.12 This spurred the development of
a host of other precious-metal catalysts for dehydrogenative
amide synthesis, but all suffered from the limitations of
requiring an exogenous base, the need for a stoichiometric
hydrogen acceptor, low productivity (TONs < 100), or a
RESULTS AND DISCUSSION
■
Catalytic Studies. Several independent research endeavors
(including within our laboratories) have reported the successful
Received: April 6, 2017
© XXXX American Chemical Society
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Scheme 1. Metal-Promoted Pathways for Dehydrogenative Amidation
Table 1. Dehydrogenative Amidation of Methanol Catalyzed
a
by 1
Figure 1. Efficient (a) ruthenium and (b) iron catalysts for
dehydrogenative coupling of alcohols and 2° amines.
application of iron-pincer catalysts of the type (RPNP)Fe(H)-
i
(CO) (R = Pr, Cy) for the dehydrogenation of alcohols to
esters,32 ketones,32 or carbon dioxide.33,34 Recently, we also
described the use of 1 in the catalytic base-free hydrogenation
of amides,35 which suggests it may have the potential to
catalyze the dehydrogenative formation of amides. Due to the
success of 4-formylmorpholine as a substrate in prior amide
hydrogenation experiments,35 investigations into the micro-
scopic reverse reaction began with attempts to couple
morpholine and methanol in the presence of 1. An initial
experiment was performed using a 4:1 amine:alcohol ratio and
a 0.1 mol % loading of 1 in 10 mL of dioxane at 80 °C for 8 h.
Despite the lack of optimization, this reaction yielded a
promising TON of 297 for the formation of 4-formylmorpho-
line. Using this reaction as a benchmark, the solvent, reaction
volume, time, temperature, and substrate ratio were all varied to
generate an optimized set of reaction conditions (Figures S1−
S5 in the Supporting Information). Using these optimized
conditions (illustrated in Table 1), a TON of 503 was observed
for the formation of 4-formylmorpholine (entry 3), which rivals
the highest TONs reported for ruthenium catalysts in
dehydrogenative amidation using secondary amines.11−28 The
TON was confirmed by NMR analysis of the 4-formylmorpho-
line product and by collection of the dihydrogen produced
(86% of expected H2 was collected). Encouraged by the activity
of 1 with traditionally more difficult secondary amines, the
substrate scope of dehydrogenative amidation was further
explored (Table 1). Overall, 1 is extremely effective at amide
production using cyclic secondary amines (entries 1−3), with a
maximum TON of 600 observed in the formylation of 1,2,3,4-
tetrahydroisoquinoline. However, the catalytic activity appears
a
Reaction conditions: 3 μmol of catalyst (0.1 mol %), 3 mmol of
alcohol, and 12 mmol of amine in 5 mL of THF at 80 °C for 8 h. Each
entry is an average of two trials, and the TON was determined by GC
analysis of amide production unless otherwise indicated. Determined
by H NMR spectroscopy. Only one trial.
b
c
1
strongly correlated to the size of the substituents on the amine.
For example, we compared the sterically restricted cyclic
amines to substrates with even small linear substituents, such as
ethyl, which shows a significant drop in TON down to
approximately 200 (entry 4). This effect is further demon-
strated as the amine substituents increase in size (entries 5−7),
with only trace conversion observed for the phenyl and
isopropyl derivatives. Attempts to generate diamides starting
from cyclic amides (entries 8 and 9) were also unsuccessful,
although previous studies from our laboratories suggest that
this may be due to a competing 1,2-addition reaction between
secondary amides and 1.35 Initial studies into extending the
B
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scope of amines to include primary amine substrates have
indicated a propensity for 1 to further substitute the initially
formed formamides to yield ureas (among other products).
Explorations into optimizing and controlling the selectivity of
this process will be addressed in future work. Despite the
aforementioned steric limitations on the amine substrates, the
ability of 1 to catalyze the production of a range of formamides
using methanol is significant, as small alcohols have to
overcome a larger activation energy for dehydrogenation,
which makes them incompatible with many catalysts.36
Additionally, formamides are highly desirable products due to
both their role as organic intermediates and their high
biological activities, making them integral to many pharma-
ceuticals.27 Most of the few existing methods for using
methanol as a “green” C1 building block in place of hazardous
formylating reagents in formamide syntheses require harsh
conditions, exhibit long reaction times, and show limited
scope.27 Of the many previously reported catalysts for amide
formation from alcohols and amines, only three (two
ruthenium-based and one manganese-based) were at all capable
of formamide production, and then only with low TONs
(≤50).23,27,30
removed from the dehydrogenation site (entries 4 and 5). The
absence of catalysis in the presence of 2,2,2-trifluoroethanol
(entry 6) is likely due to its relative acidity and its electron-
withdrawing substituent. Interestingly, methanol far outper-
forms the other alcohols explored. When this observation is
combined with the results on the effect of sterics on the amine
substrate, it indicates that there is a strong steric effect at both
sides of the product carbonyl moiety. To some extent these
results are unsurprising, as the large substrate groups would
potentially interfere with metal-catalyzed dehydrogenation
steps in which the substrates or intermediates must pass the
four sizable isopropyl substituents of the pincer ligand.
Although the overall substrate scope exhibited by 1 remains
quite sterically limited, the high productivity observed for small
substrates suggests that the inherent activity of the iron center
is significant and could perhaps be leveraged by further
attenuation of the ancillary ligand environment.
Mechanistic Considerations. Recent investigations of
transition-metal-catalyzed dehydrogenative amidation have
nearly all proposed the same general pathway for amide
formation (Scheme 1).12,14,26 Each begins with the dehydro-
genation of the alcohol to the corresponding aldehyde followed
by trapping with either amine or an additional 1 equiv of
alcohol to generate a hemiaminal or hemiacetal intermediate,
respectively. Dehydrogenation of an intermediate hemiaminal
would directly afford an amide, while oxidation of the
hemiacetal would yield an ester which could then produce
amide via a transamidation process. However, the exact
mechanisms for dehydrogenative amidation are likely catalyst
and system dependent. For example, many ruthenium catalysts
employ base additives to achieve optimum performance, which
can potentially serve many different roles. These include
enhancing coordination of the alcohol to the metal,15
facilitating amine to aldehyde proton transfer, obviating
hemiaminal formation,26 and promoting ester transamidation.19
Prior studies within our laboratories demonstrate that 1 is
quite capable of promoting ester formation, achieving a TON
of 107 over just 12 min for the methanol to methyl formate
conversion under conditions similar to those used in this work
for amidation.33 In addition, amidation experiments using
catalyst 1 and morpholine with methyl formate in place of
alcohol yielded substantial quantities of 4-formylmorpholine
(Figure 2).37 These observations suggest that the lower
pathway illustrated in Scheme 1 is at least viable for 1-catalyzed
amidation. However, further mechanistic experiments substitut-
ing benzaldehyde for alcohol during the amidation process also
afforded the corresponding amide product (Figure 2), which
validates the hemiaminal-dependent path for amide produc-
tion.37 Since these preliminary investigations indicate that both
of the Scheme 1 pathways are competent for 1, it is clear that a
more exacting and extensive mechanistic undertaking will be
required to elucidate the precise path of 1-catalyzed amidation.
The success of 1 in dehydrogenating a challenging substrate
such as methanol motivated investigation into the alcohol
substrate scope for amidation. Using morpholine as the amine
substrate, the catalytic activity of 1 was examined with a range
of primary alcohols (Table 2). Similar to the observations with
Table 2. Alcohol Dehydrogenation in the Presence of
a
Morpholine Catalyzed by 1
entry
alcohol
CH3OH
TON
1
2
3
4
5
6
503
50
CH3CH2OH
CH3(CH2)5OH
C6H5(CH2)2OH
C6H5CH2OH
CF3CH2OH
13
10
10
b
0
a
Reaction conditions: 3 μmol of catalyst (0.1 mol %), 3 mmol of
alcohol, and 12 mmol of amine in 5 mL of THF at 80 °C for 8 h. Each
entry is an average of two trials, and the TON was determined by GC
b
analysis of amide production unless otherwise indicated. Determined
1
by H NMR spectroscopy.
amines, the performance of 1 is highly sensitive to the steric
profile of the alcohol (entries 1−3). This effect on catalytic
activity remains even when the larger substituent is slightly
Figure 2. Iron-catalyzed coupling of benzaldehyde and methyl formate with morpholine.
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During the course of the mechanistic and catalytic experi-
ments described above, it was noted that the reaction solution
reversibly changed color. When the catalytic experiments were
assembled, the solution of 1 and amine immediately changed
from deep red to yellow-orange upon addition of the alcohol
substrate at room temperature. When the solution was heated
during catalysis, the color would quickly revert back to a shade
of deep red resembling its original hue. In order to ascertain
any mechanistic implications this color change might entail, in
situ NMR spectroscopic studies using morpholine and
methanol were performed. Multiple experiments showed that
the color change and corresponding changes to the 31P and 1H
NMR spectra were exclusively dependent on the addition of
alcohol (Figure S1 in the Supporting Information), whereas
treatment of 1 with only morpholine produced no observable
reaction. The reaction of 1 with methanol was examined using
variable-temperature NMR spectroscopy, which indicated an
equilibrium between 1 and the iron-methoxy species (iPrPN-
(H)P)Fe(H)(OCH3)(CO) (2) formed by the addition of
methanol across the Fe−N bond. At all observed temperatures
between 22 and 70 °C, only one 31P NMR resonance was seen,
although its chemical shift changes with temperature (Figure
3). This is indicative of a rapid equilibration between 1 and 2
between free and iron-activated methanol. At −80 °C, two
distinct peaks for the bound and free 13CH3 fragment were
observed in the 13C{1H} spectrum and a sharp resonance for 2
was seen at 93.2 ppm in the 31P NMR spectrum (Figure S2 in
the Supporting Information). A proton-coupled 13C spectrum
showed that the labeled carbon is still attached to three
protons, supporting the presence of an iron-methoxy species
(Figure S2). The exact position of the 31P{1H} NMR peak for 2
depends on both the temperature and the number of
equivalents of methanol, due to the equilibrium described
above.
The formation of 2 via deprotonation of methanol is likely an
off-cycle reaction that competes with catalytic amidation. As
mentioned above and illustrated in Scheme 1, the dehydrogen-
ation of an alcohol to an intermediate aldehyde has been
implicated in most related amidation processes.12,14,26 Our
prior experimental and computational studies of 1-catalyzed
methanol dehydrogenation have found that this reaction
proceeds via a concerted transfer of the hydrogenation atoms
associated with the methanol O−H and C−H bonds.
Dehydrogenation pathways involving intermediates analogous
to complex 2 were found to be significantly higher in energy.33
Thus, while formation of 2 may have some kinetic relevance to
catalytic amidation, it is likely not directly on its pathway and
the high-temperature catalytic conditions presumably minimize
the significance of 2 in amide formation.
CONCLUDING REMARKS
■
The five-coordinate iron complex 1 exhibits the highest
productivity yet reported for base-metal-catalyzed intermolec-
ular dehydrogenative coupling of alcohols and amines to
amides. Despite its notable success in producing formamides,
the primary drawback of 1 is the steric limitation of its alcohol
and amine substrate scope, which will likely obviate more
widespread use in synthetic methodology. However, this iron-
mediated amidation provides an intriguing preference for
secondary amines, which is a complement to the leading
precious-metal catalysts, which work best with primary amines.
In fact, the TONs of up to 600 for tertiary amide production far
exceed the performance of any catalyst to date. The native
activity and divergent selectivity of 1-catalyzed dehydrogenative
amidation strongly motivate further investigation into the
mechanism of this process as well as catalyst development.
Perhaps by alteration of the steric environment about the
catalyst, the substrate scope for amidation can be widened
beyond methanol and relatively small amines. Likewise,
understanding the mechanistic origins of the preference for 1
to amidate secondary amines could further expand transition-
metal-mediated synthetic methods in this area. Both of these
endeavors are the current subjects of investigation in our
laboratories.
Figure 3. Variable-temperature 31P NMR spectra indicating an
equilibrium between 1 and 2 in the presence of 6 equiv of methanol.
The sample was dissolved in benzene-d6.
EXPERIMENTAL DETAILS
■
General Considerations. All manipulations were carried out
under a nitrogen or argon atmosphere using standard Schlenk,
vacuum, cannula, or glovebox techniques. Catalysts 1 and (iPrPNHP)-
Fe(H)(HCO2)(CO) (1-formate) were prepared as previously
described.38 Amide products (for gas chromatography response
factors) that were not commercially available were prepared using
previously reported procedures.39,40 All other chemicals were
purchased from Aldrich, Fisher, Strem, Synthonix, Oakwood
Chemicals, VWR, or Cambridge Isotope Laboratories. Liquid amine
and alcohol substrates were dried over calcium hydride or sodium
hydride, purified by vacuum transfer or distillation, and stored over 3 Å
on the time scale of the NMR experiment, and the position of
the resonance represents an average value for the chemical
shifts of the two species present in solution. The change in the
31P NMR chemical shift suggests that 1 is favored at high
temperatures and 2 is preferred at lower temperatures, as
expected for a bimolecular to unimolecular reaction. The
identity of 2 was confirmed using 13CH3OH labeling and low-
temperature NMR studies, which slowed the exchange rate
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molecular sieves. Solid substrates were purified by sublimation,
followed by recrystallization (if necessary). Bulk solvents were dried
and deoxygenated using literature procedures.41 NMR solvents were
dried over 3 Å molecular sieves and then used without further
manipulation or were dried over sodium and then vacuum-transferred
prior to use. Hydrogen and carbon dioxide were purchased from
Airgas and were used as received. 1H, 13C, and 31P NMR spectra were
recorded on Bruker 300 MHz Avance II+, 300 MHz DRX, 500 MHz
DRX, and 600 MHz spectrometers at ambient temperature, unless
otherwise noted. Chemical shifts are reported in ppm; J values are
ORCID
Nilay Hazari: 0000-0001-8337-198X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support by Brown University, the
Curators of the University of Missouri, and the National
Science Foundation (CHE-1350047). N.H. and W.B. are
fellows of the Alfred P. Sloan Foundation.
1
given in Hz. H 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.42 Gas chromatography
was performed on a Thermofisher Scientific Trace 1300 Series gas
chromatograph with an FID using helium as the carrier gas.
General Procedure for the Formation of Complex 2. In a
drybox, 5 mg of complex 1 was dissolved in either C6D6 or d8-THF in
a 20 mL scintillation vial and then transferred to a J. Young tube. The
tube was then sealed, removed from the glovebox, and degassed, and 6
equiv of methanol or 13C-labeled methanol were added via calibrated
gas bulb.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail for W.B.: bernskoetterwh@missouri.edu.
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DOI: 10.1021/acs.organomet.7b00258
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