A Multicatalytic Approach to the Hydroaminomethylation of α-Olefins

Article abstract of DOI:10.1002/anie.201811297

We report an approach to conducting the hydroaminomethylation of diverse α-olefins with a wide range of alkyl, aryl, and heteroarylamines at relatively low temperatures (70–80 °C) and pressures (1.0–3.4 bar) of synthesis gas. This approach is based on sim

Full text of DOI:10.1002/anie.201811297

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Accepted Article
Title: Multicatalytic Approach to the Hydroaminomethylation of α-
Olefins
Authors: Steven Hanna, Jeffery C Holder, and John F. Hartwig
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10.1002/anie.201811297
Angewandte Chemie International Edition
COMMUNICATION
Multicatalytic Approach to the Hydroaminomethylation of α-
Olefins
Steven Hanna, Jeffery C. Holder, and John F. Hartwig*
Abstract: We report an approach to conducting the
hydroaminomethylation of diverse α-olefins with a wide range of alkyl,
aryl, and heteroarylamines at low temperatures (70-80 °C) and
pressures (1.0-3.4 bar) of synthesis gas. This approach is based on
simultaneously using two distinct catalysts that are mutually
compatible. The hydroformylation step is catalyzed by a rhodium
diphosphine complex, and the reductive amination step, which is
conducted as a transfer hydrogenation with aqueous, buffered sodium
formate as the reducing agent, is catalyzed by a cyclometallated
iridium complex. By adjusting the ratio of CO to H2, we conducted the
reaction at one atmosphere of gas with little change in yield. A diverse
array of olefins and amines, including hetreroarylamines that do not
react under more conventional conditions with a single catalyst,
underwent hydroaminomethylation with this new system, and the
pharmaceutical ibutilide was prepared in higher yield and under milder
conditions than those reported with a single catalyst.
olefin to form an aldehyde and reductive amination of this
aldehyde to form an amine.[2] The reaction is commonly
conducted with a rhodium-based catalyst ligated by a diphosphine
(Scheme 2A). Several limitations, such as the high pressure of
synthesis gas (usually around 60 bar) required to achieve
acceptable yields,[2a, 2b] have diminished the utility of this reaction.
In addition, self-condensation of the aldehyde, hydrogenation of
the aldehyde, and hydrogenation of the olefin have been reported
to compete with hydroaminomethylation.[2a]
Hydroaminomethylation is difficult to achieve, in part, because
the properties of the most active catalysts for hydroformylation are
quite different from those of the most active catalysts for reductive
amination.[3] Moreover the reductive amination process must not
be strongly inhibited by carbon monoxide. A single catalyst that
meets these criteria and catalyzes hydroaminomethylations at low
pressures and temperatures has not been identified. In 2003,
Beller reported one of the most active and regioselective systems
comprising the combination of [Rh(COD)2]BF4 with Xantphos, but
these reactions were conducted with 40 bar of syngas at 125 °C
(Scheme 2A).[4] Hydroaminomethylations reported by Eilbracht,
Alper, Whiteker, Zhang, and others occur under similar
conditions.[5] A set of hydroaminomethylations reported by Beller
occurred at the lower temperature of 60 °C. However, these
reactions were limited to those of vinylarenes, and high pressures
(30 bar, 1:5 CO:H2) were still required. [6]
Amines are ubiquitous in industrial, biological, and synthetic
chemistry. Many industrial products either contain linear amines
or are synthesized from amines,[1] and some of the most
commonly prescribed pharmaceuticals contain 1-aminoalkyl
groups (Scheme 1). Such amines are most commonly
synthesized by the amination of alcohols, the reductive amination
of aldehydes, or the reduction of amides, nitriles, or nitro
compounds.[1] However, the starting materials for these
processes are often synthesized from olefins; therefore, a method
for the synthesis of amines from olefins would be more direct, less
expensive, and more environmentally benign than the multi-step
alternatives.
Scheme 2. Approaches to hydroaminomethylation
Scheme 1. APIs containing aminoalkyl groups
The hydroaminomethylation of olefins is an atom-economical
and operationally simple reaction involving hydroformylation of an
We envisioned a new approach in which two catalysts, one for
each step, would react by mechanisms that are distinct and
independent from each other, enabling hydroaminomethylation to
occur under conditions that are milder than those with a single
catalyst.[7] Beller and Luo published hydroaminomethylations
conducted with a single phosphine and two metals, but these
[a]
S. Hanna, Dr. J. C. Holder, Prof. J. F. Hartwig
Department of Chemistry, 718 Latimer Hall
University of California, Berkeley
Berkeley, CA 94708
jhartwig@berkeley.edu
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10.1002/anie.201811297
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reactions still required high pressures of synthesis gas and high
temperatures (Scheme 2B).[8] Following a different design, Xiao
and Han published hydroaminomethylations catalyzed by the
combination of a rhodium-based catalyst for the hydroformylation
step and a chiral phosphoric acid for the reductive amination step
that form enantioenriched, branched amines from α- and β-
functionalized olefins (Scheme 2C). However, these systems
under the conditions in Table 1. This reactivity of the reductive
amination catalyst toward hydroformylation leads to low n:iso
ratios of the amine product. Amine 3aa also formed in low yields
in the presence of catalyst C6 (entry 8). All of the
hydroaminomethylations conducted with catalysts C1-C6 (entries
1-8) proceeded to high conversions; the major side products of
the reactions formed from self-condensation of undecanal.
have
not been
shown
to
catalyze
linear-selective
Table 1. Evaluation of conditions for the hydroaminomethylation of 1-decene
with aniline
hydroaminomethylations of unfunctionalized alkenes, and the
organic catalyst requires an expensive Hantzsch ester to reduce
the imine intermediate.[7a, 7b, 9]
Herein, we report a linear-selective hydroaminomethylation of
α-olefins catalyzed by two distinct metal complexes and an
approach to the reductive amination step not applied previously
to hydroaminomethylation (Scheme 2D). A rhodium-diphosphine
complex catalyzes the hydroformylation step, and a phosphine-
free, cyclometallated iridium complex catalyzes the reductive
amination step by transfer hydrogenation. Key features of this
work include the identification of a catalyst for reductive amination
that is not poisoned by CO and the use of buffered formic acid for
the reduction step. With this system, aromatic, heteroaromatic,
and aliphatic amines are formed in high yields and in high
regioselectivities with pressures of synthesis gas and
temperatures that are significantly lower than those used
previously for hydroaminomethylation.
Our
strategy
for
a
low-pressure,
multicatalytic
hydroaminomethylation was based on the hypotheses that the
high pressures of hydrogen in existing systems for
hydroaminomethylation are required to ensure that reductive
amination is faster than self-condensation of the aldehyde and
that the reductive amination step of hydroaminomethylation is
slow because catalysts for this step tend to be inhibited by carbon
monoxide. In this case, a reductive amination catalyst that is
unaffected by carbon monoxide could be combined with a suitable
hydroformylation catalyst to conduct hydroaminomethylations at
low pressures of synthesis gas. A complex that catalyzes
reductive amination by transfer hydrogenation might meet this
criterion.
To test this reaction design, we studied the
hydroaminomethylation of 1-decene (1a) with aniline (2a) in the
presence of formic acid, the highly active and selective
hydroformylation catalyst generated from Rh(CO)2(acac) and
BISBI, and various complexes known to catalyze the transfer
hydrogenation of imines and iminium ions (Table 1). The most
well-known catalysts for reductive amination by transfer
hydrogenation consist of a metal capable of transferring a hydride
and a ligand capable of transferring a proton to a polarized
multiple bond.[10] However, amine 3aa formed in poor yield from
olefin 1a in the presence of ruthenium diamine complexes C1 and
C2 (entries 1–4), even though these complexes are known to be
active for transfer hydrogenation of imines. The group 9
congeners (catalysts C3-C5) of catalysts C1 and C2 are active for
To increase the rate of reductive amination of undecanal
relative to that of its self-condensation, we sought catalysts for
transfer hydrogenation that might be more stable to carbon
monoxide than catalysts C1-C6. Reports that catalyst C7 is more
active for the reduction of N-p-anisylketimines than catalyst C4
and the robustness of catalyst C7 endowed by cyclometallation
prompted us to attempt hydroaminomethylations with catalyst C7
as a catalyst for reductive amination.[12]
the
reductive
amination
of
aldehydes
by
transfer
hydrogenation.[11] However, amine 3aa formed with low
regioselectivity and in poor yield in the presence of catalysts C3,
C4, and C5 and in the presence of Rh(CO)2(acac) and BISBI
(entries 5–7). Control experiments indicated that complexes C3-
C5 either degrade into unselective catalysts for hydroformylation
or are themselves unselective catalysts for hydroformylation
Initial studies with catalyst C7 showed that amine 3aa formed
in only 30% yield from olefin 1a, CO, H2, and amine 2a in the
presence of catalyst C7 and the combination of Rh(CO)2(acac),
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and BISBI with a 5:2 HCO2H:Et3N azeotrope as the reducing
agent (entry 11). On the basis of prior literature showing that the
reductive amination of acetophenone with p-anisidine catalyzed
by complex C7 occurs significantly more rapidly with an aqueous
sodium formate buffer at pH 4.8 as the reducing agent than with
a 5:2 HCO2H:Et3N azeotrope as the reducing agent,[13],[14] we
conducted the hydroaminomethylation of olefin 1a with amine 2a
with this reducing agent in the presence of C7. Amine 3aa formed
in 91% yield under these conditions (entry 10). Amine 3aa formed
in lower yields in the presence of XantPhos and DPEPhos than in
the presence of BISBI (entries 11–12), and the product did not
form in the absence of formate (entry 13). The
hydroaminomethylation occurred at lower loadings of the two
catalysts with only a small sacrifice in yield (entries 14-15). Amine
3aa formed in 8% yield and 68:32 n:iso in the presence of catalyst
C7 with no Rh(CO)2(acac) present (entry 16), indicating that
catalyst C7 is only slightly active towards hydroformylation under
the developed conditions. Amine 3aa did not form in the absence
of a reductive amination catalyst (entry 17).
bifunctional mechanism.[12] Instead, Xiao’s catalyst transfers a
hydride to an iminium ion that is formed by protonation of an imine
or enamine in an acidic medium.[12]
The scope of olefins that undergo this hydroaminomethylation
is illustrated by the examples in Table 2. Phenols (3ca),
malonates (3da), nitriles (3ea), enolizable ketones (3fa), allylic
acetates (3ga), allylic alcohols (3ha), and disubstituted olefins
(3ka) were all tolerated. Olefins bearing electron-withdrawing
groups in the allylic position reacted with excellent
regioselectivities (1b, 1c, 1d, 1g, 1h); such β-functionalized
olefins often undergo hydroformylations with low n:iso ratios, due
to their tendencies to isomerize to internal olefins. Sterically
hindered α-olefins (1g, 1i, 1j, 1k) also underwent
hydroaminomethylation. As expected, the regioselectivities of the
reactions of these alkenes were higher than those of reactions of
less
hindered
alkenes.
In
addition,
the
double
hydroaminomethylation of olefin 1l proceeded in high yield and
with high regioselectivity.
Table 2. Hydroaminomethylations of various olefins with aniline
Table 3. Hydroaminomethylations of methyl eugenol with various arylamines
We attribute the high yields and regioselectivities of the
reaction in entry 10 to several factors. First, Xiao’s
cyclometallated catalyst is not significantly inhibited by low
pressures of CO; control experiments indicated that the yield of
the reductive amination of undecanal catalyzed by complex C7
was the same in the absence of CO as in the presence of 1.7 bar
of CO. In contrast, complexes C1, C2 and C6 were poisoned by
CO, even at this low pressure (see the supporting information for
details). Second, Xiao’s catalyst is compatible with the aqueous
HCO2Na buffer, a mild, inexpensive hydrogen surrogate. Finally,
Xiao’s catalyst does not hydrogenate imines by a metal-ligand
The scope of arylamines that undergo hydroaminomethylation
was studied with the olefin methyl eugenol (1b) as the coupling
partner. The results are given in Table 3. Both electron-poor (2b,
2c, 2e) and
electron-rich (2d) anilines underwent
hydroaminomethylation. Anilines bearing ortho substituents (2f)
and
those
bearing
ketones
(2e)
also
underwent
hydroaminomethylation.
The scope of
heteroarylamines
that undergo
hydroaminomethylation with olefin 1b is also shown in Table 3.
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Heteroarylamines are widespread in pharmaceuticals and
agrochemicals, but hydroaminomethylations with such regents
are limited.[15] For reference, we conducted the reaction of olefin
1b with 2-aminopyridine (2g) under standard conditions for
hydroaminomethylation (125 °C, 40 bar 1:5 CO:H2) with the single
catalyst formed from the combination of [RhCOD2]BF4 and
Xantphos. Only trace amounts of amine 3bg formed; the major
species present in the crude reaction mixture was the starting
olefin 1b.[16] In contrast, the reactions of methyl eugenol with
lower yields and required pressures of syngas that are much
higher than those in the current work.[5e]
heteroarylamines,
aminoindoles (2i),
including
aminopyridines
(2j,
(2g,
2k),
2h),
and
aminoquinolines
aminodibenzofurans (2l) occurred in good yield under the
conditions we developed with two catalysts. Even
heteroarylamines capable of chelating metal catalysts (2k)
reacted. This contrast in reactivity demonstrates the unusual
compatibility of the new system for hydroaminomethylation with
biologically important heteroarenes.
Scheme 3. Synthesis of Ibutilide
Finally, the hydroaminomethylations reported in this work can
be conducted easily on large scales and at atmospheric pressure
of syngas. The hydroaminomethylation of 6 mmol of methyl
eugenol with aniline gave 1.24 g of amine 3ba (71% yield,
Scheme 4. By adjusting the ratio of CO to H2 to 1:2 CO:H2, the
reaction of 1-decene (1a) with aniline (2a) formed N-undecyl
aniline (3aa) in 65% yield at a total pressure of only 1 atm at 70 °C
(Scheme 5).
Alkylamines might be expected to be quenched by the acidic
buffer containing formic acid, but both primary and secondary
alkylamines underwent hydroaminomethylation under the
conditions we developed with two catalysts and a pH 4.8 formate
buffer (Table 4). Both cyclic (2m, 2n, 2o, 2p) and acyclic (2q, 2r,
2s) secondary amines underwent the hydroaminomethylation.
Sterically hindered aliphatic amines were less reactive towards
hydroaminomethylation than unhindered aliphatic amines,
presumably due to slow reduction of sterically hindered iminium
ions. Primary aliphatic amines (2t) also underwent
hydroaminomethylation to form secondary amines without the
formation of tertiary amines.
2a
( )
PhNH2
CO:H2 (1:1, 3.4 bar)
O
O
O
O
NHPh
HCO2Na Buffer
Rh(CO)2(acac), BISBI,
C7
71%, 1.2 g
92:8
6 mmol
1b
3ba
Table 4. Hydroaminomethylations of methyl eugenol with various aliphatic
amines
Conditions: methyl eugenol (6 mmol), aniline (9 mmol), pH 4.8 aqueous sodium
formate buffer (6 mL), CO:H2 (1:1, 3.4 bar), Rh(CO)2(acac) (0.5 mol%), BISBI (2.5
mol%), Xiao's catalyst (1 mol%), 9:1 PhMe:MeOH (30 mL), 80 °C, 20 h.
Scheme 4. Hydroaminomethylation on a 6-mmol scale
Scheme 5. Hydroaminomethylation at atmospheric pressure
In summary, we have developed a scalable, linear-selective,
dual-catalytic hydroaminomethylation of α-olefins occurring at low
temperature and pressure by exploiting the combination of a
catalyst for hydroformylation and
a catalyst for reductive
amination that is active under carbon monoxide and that reduces
imines by transfer hydrogenation. The pressures and
temperatures of the reaction are the lowest reported for linear-
selective hydroaminomethylations, and the reactions can even be
conducted at atmospheric pressure of synthesis gas. The reaction
occurs with a broad range of olefins and amines and is uniquely
suitable for the preparation of a wide range of medicinally relevant
heteroarylamines. Efforts to further increase the activity of dual
catalysts and the scope of reactants are ongoing.
To demonstrate further the applicability of this work to the
preparation of medicinally relevant amines, we synthesized amine
3mt, the active ingredient in a drug sold under the generic name
ibutilide (Scheme 3). Under the conditions in Scheme 3, olefin 1m
underwent hydroaminomethylation in 76% yield. Previous
examples of this hydroaminomethylation occurred in significantly
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COMMUNICATION
[15] Beller
has
shown
that
1,1-diphenylethylene
undergoes
Acknowledgements
hydroaminomethylations with piperidines bearing remote pyridyl and
pyrimidyl groups, but this olefin undergoes hydroaminomethylation with
4-aminopyridine in low yield. M. Ahmed, C. Buch, L. Routaboul, R.
Jackstell, H. Klein, A. Spannenberg, M. Beller, Chem. Eur. J. 2007, 13,
1594-1601.
This work was supported by the Director, Office of Science, U.S.
Department of Energy, under contract No. DE-AC02-05CH1123.
Jeffrey C. Holder thanks the National Institutes of Health for sup-
port through 5F32GM112312.
[16] Reaction Conditions: 0.5 mmol methyl eugenol, 0.5 mmol 2-
aminopyridine, 40 bar CO:H2 (1:5), [Rh(COD)2]BF4 (0.1 mol%),
Xantphos (0.4 mol%), 1.5 mL PhMe:MeOH (1:1), 125 °C, 20 h
Keywords: hydroaminomethylation • bimetallic • multicatalytic •
transfer hydrogenation • hydroformylation • reductive amination
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[14] The precise pH of the buffer strongly influences the outcomes of
reductive aminations with Xiao's catalyst. Under basic conditions, neither
imines nor ketones are protonated, and the reduction does not occur. In
contrast, under highly acidic conditions, amines, ketones, and imines are
protonated and both the chemoselectivity for the reduction of C=N bonds
and the rate of the reductive amination are low. See reference 14.
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COMMUNICATION
Steven Hanna, Jeffery C. Holder, and
John F. Hartwig*
Page No. – Page No.
Multicatalytic Approach to the
Hydroaminomethylation of α-Olefins
Two cats make HAM: Two distinct, mutually compatible catalysts enable the
hydroaminomethylation of alkenes at or near atmospheric pressure of syngas and
just 80 °C. The hydroformylation step is catalyzed by a rhodium diphosphine
complex, and the reductive amination step, which is conducted as a transfer
hydrogenation with aqueous, buffered sodium formate as the reducing agent, is
catalyzed by a cyclometallated iridium complex.
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