Tailored Cobalt-Catalysts for Reductive Alkylation of Anilines with Carboxylic Acids under Mild Conditions

Article abstract of DOI:10.1002/anie.201806132

The first cobalt-catalyzed hydrogenative N-methylation and alkylation of amines with readily available carboxylic acid feedstocks as alkylating agents and H₂ as ideal reductant is described. Combination of tailor-made triphos ligands with cobalt(II) tetrafluoroborate significantly improved the efficiency, thus promoting the reaction under milder conditions. This novel protocol allows for a broad substrate scope with good functional group tolerance, even in the presence of reducible alkenes, esters, and amides.

Full text of DOI:10.1002/anie.201806132

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Accepted Article
Title: Tailored Cobalt-Catalysts for Reductive Alkylation of Anilines with
Carboxylic Acids under Mild Conditions
Authors: Weiping Liu, Basudev Sahoo, Anke Spannenberg, Kathrin
Junge, and Matthias Beller
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806132
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10.1002/anie.201806132
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Tailored Cobalt-Catalysts for Reductive Alkylation of Anilines
with Carboxylic Acids under Mild Conditions
Weiping Liu, Basudev Sahoo, Anke Spannenberg, Kathrin Junge, and Matthias Beller*
Abstract: The first cobalt-catalyzed hydrogenative N-methylation
and alkylation of amines with readily available carboxylic acid
feedstocks as alkylating agents and H2 as ideal reductant is
described. Combination of tailor-made triphos ligands with cobalt(II)
tetrafluoroborate significantly improved the efficiency, thus promoting
the reaction under milder conditions. This novel protocol allows for a
broad substrate scope with good functional group tolerance, even in
the presence of reducible alkenes, esters and amides.
N-Alkylation of amines has a long-lasting yet highly perceptible
interest among synthetic chemists, because the resulting
products are widely featured in natural products, pharmaceutical
drugs, agrochemicals and dyes, fine chemicals and many
more.[1] Traditional syntheses of N-alkylated amines from
ammonia, primary or secondary amines with alkyl halides
generate at least stoichiometric amounts of halide waste and
often this transformations suffer from selectivity (Figure 1a)[2].
Although the reductive alkylation using aldehydes or ketones as
the alkyl source represents
Figure 1. Synthesis of N-alkylated amines
a
greener approach,[3] their
availability and sensitivity sometimes restricts their utility (Figure
1b). To address these problems, application of readily available
and more stable carboxylic acids for the reductive alkylation of
amines emerged as an attractive alternative in recent years.[4]
Initially, such reactions were realized using stoichiometric
We started our investigations by testing the reductive ethylation
of aniline (1a) with acetic acid (2a) and hydrogen in the
presence of cobalt salts and a series of phosphine ligands.
While all tested ligands (PPh3, dppe, xantphos and tetraphos)
remained inactive, the desired N-ethylaniline (3aa) was obtained
amounts of metal borohydrides or silane reductants (Figure
.
in low yield (17%) in the presence of Co(BF4)2 6H2O and triphos
4i-k]
1c).[4d-g,
In 2015, we demonstrated the feasibility of this
(L1), under relatively mild conditions (100 °C, 40 bar H2) (Table
S1).[10] Prompted by the critical role of this ligand, we became
interested in the synthesis of other triphos ligands (L2-L6) to
improve efficiency (Figure 2). Unfortunately, only trace amounts
of 3aa could be detected when ligand L2 was employed under
these conditions, apparently showing poor reactivity due to the
presence of bulky substituents at phosphorus center.
transformation utilizing H2 as green and atom-efficient reductant
in the presence of a ruthenium/triphos[5] catalyst. Unfortunately,
in this original method, relatively harsh conditions (160 °C, 60
bar) and expensive and air-sensitive additives were required
(Figure 1d).[4h]
A rising trend in catalytic hydrogenations is the utilization of non-
noble metals due to their abundance and lower price. In this
context, also cobalt[6]-based catalytic systems, particularly
containing pincer[7] as well as tri- or tetraphos[8] ligands attracted
substantial attention. Inspired by the seminal report on the
hydrogenation of acids and esters to alcohols by Elsevier and de
Bruin et al.,[9] herein we describe a convenient and practical
cobalt-catalyzed N-alkylation of amines. The presence of tailor-
made triphos ligands permits increased efficiency/activity using
carboxylic acids and H2 under milder conditions compared to
previous related ruthenium catalysis[4h] (Figure 1, bottom).
100%
80%
60%
40%
20%
0%
90%
81%
55%
40%
17%
<3%
L2
L1
L3
L4
L5
L6
[*]
Dr. W. Liu, Dr. B. Sahoo, Dr. A. Spannenberg, Dr. K. Junge, Prof.
Dr. M. Beller
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert-Einstein-Straße 29a
18059 Rostock, Germany
Figure 2. Co-catalyzed reductive ethylation of aniline. Reaction conditions:
1a (0.5 mmol), 2a (1.0 mmol), Co(BF4)2.6H2O (3.0 mol %), ligand (6.0 mol %)
and 1,4-dioxane (2.0 mL) under H2 (40 bar), 100 °C for 24 h. GC yields.
E-mail: matthias.beller@catalysis.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under
The 3,5-dimethyl-substituted triphos L3 and p-methyl-substituted
triphos L4, which have previously been reported to exhibit higher
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activities for carbon dioxide hydrogenation,[8e] also displayed
higher efficiency in our benchmark reaction. Surprisingly, the
yield of 3aa was dramatically increased up to 90% applying the
more electron-rich ligand L5 with p-methoxy substituents.
Further replacing the methyl group in the ligand skeleton by a
phenyl group provided L6, which led to a slightly lower yield of
3aa. It is noteworthy that Ru(acac)3/L5 failed to offer the desired
product under otherwise identical reaction conditions,
highlighting the superiority of this cobalt system compared to
ruthenium system.[4h]
Encouraged by this success, we explored the reactivity of
anilines with diverse substitution patterns with acetic acid
(Scheme 1). The mono-ethylated products were obtained in all
cases with good yields and excellent selectivity irrespective of
the substituents at ortho-, meta- or para-position. Functional
group tolerance is demonstrated among others with substrates
including methylthio, fluoro, chloro and alcohol substituents.
Notably, also tertiary amines can be obtained either from the
secondary amine directly in high yield or by increasing the
amount of acid.
Scheme 2. N-Alkylation of aniline with carboxylic acids. Reaction conditions:
1a (0.5 mmol), 2 (1.0 mmol), Co(BF4)2.6H2O (3.0 mol %), triphos(p-anisole) (6.0
mol %) and 1,4-dioxane (2.0 mL), isolated yields. [a] 140 °C, H2 (40 bar). [b]
GC yields. [c] 140 °C, H2 (20 bar). [d] 2 (1.5 mmol). [e] 2 (2.0 mmol).
Among the different alkylations, the simple methylation[4e, 4i, 4k, 12]
is probably most important and meaningful due to its so-called
magical effect in drug discovery.[13] In this respect, biomass-
derived formic acid (FA) would be an inexpensive and
sustainable resource for methylations. Delightfully, the
.
Co(BF4)2 6H2O/triphos(p-anisole)-catalyzed methylation of aniline
derivatives proceeded in an efficient manner (Scheme 4).
Additionally, N,N-dimethylaniline (4a) can be formed as the sole
product when 3.0 equiv. of FA were used. Notably, 2-
methyltetrahydroquinoline was also methylated efficiently by this
methodology.
Scheme 1. N-Ethylation of anilines with acetic acid. [a] GC yields.
Subsequently, the reductive alkylation of aniline with different
carboxylic acids
2
was investigated (Scheme 2).
A
representative set of long chain aliphatic carboxylic acids, cyclic
acids as well as aromatic acids 2 were amenable to our novel
cobalt-catalyzed reductive alkylation, thereby furnishing the
alkylated anilines in moderate to good yields and excellent
chemoselectivity. Interestingly, among various natural fatty acids,
caprylic acid, lauric acid and stearic acid which are abundant
renewables e.g. from coconut milk and oils, also underwent this
hydrogenative alkylation in high efficiency to deliver the
corresponding amines. Notably, as an example of -hydroxy
carboxylic acids (AHA), (L)-(+)-lactic acid provided the
corresponding racemic β-amino alcohol in 96% yield.
Exploring more demanding substrates under these conditions,
several functional groups including alkene, primary and
secondary amides and even esters, all typically sensitive to
reduction, remained stable in this novel method (Scheme 3). A
substrate featuring the scaffold of a canonical transient receptor
potential (TRPC3) channel inhibitor[11] 1u was successfully
ethylated using acetic acid (Scheme 3).
Scheme 3. Cobalt-catalyzed alkylation of substrates bearing reducible
functional groups. [a] 100 °C. [b] 120 °C. [c] 140 °C. [d] N1,N4-
Diethylbenzene-1,4-diamine was detected as side product by GC-MS. [e] 1-
Phenylazepan-2-one was detected as side product by GC-MS.
Considering several possible pathways for the mechanism of
this homogenous[14] cobalt-catalyzed hydrogenative alkylation of
aniline, a set of mechanistic experiments was performed. Firstly,
to our surprise, the desired N-ethylaniline (3aa) was not formed
when the reaction was conducted with acetanilide (5). However,
36% of acetanilide converted to 3aa as the major product in the
presence of 1.0 equivalent of acetic acid (Scheme 5a). These
findings and good tolerance of amides as functional group (vide
supra) illustrate that amide formation prior to reduction is not
involved in the major pathway, but cannot be fully excluded.[5h, 15]
Additionally, no N-ethylaniline (3aa) formation likely ruled out the
possibility of a borrowing hydrogen process[16] when ethanol
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10.1002/anie.201806132
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instead of acetic acid (2a) was directly used as the ethyl source
(Scheme 5b).
mention that when the above mixture was used as the catalyst
under the standard conditions, the desired product 3aa was
afforded in 81%. Furthermore, the identical catalytic species
could also be detected by ESI-MS analysis during the course of
reaction.[10]
Scheme 4. N-Methylation of amines with formic acid. [a] GC yields. [b] 2o (1.5
mmol, 3.0 equiv).
Scheme 6. Proposed pathways of the cobalt-catalyzed reductive alkylation
Moreover, when acetaldehyde was directly employed as the
alkylating reagent to replace acetic acid, 42% of the desired
product 3aa was obtained along with intractable byproduct
formation which highlights the superiority and robustness of the
N-alkylation protocol with carboxylic acids compared to the
corresponding aldehyde (Scheme 5b). In a more important
experiment employing the stable aldimine (7) as the substrate
under standard conditions, 3ai was achieved in 72% yield with
24% aniline (1a) formation due to imine hydrolysis (Scheme 5c).
Figure 3. Molecular structure of the cation of [Co(triphos(p-anisole))OAc][BPh4]
(9) in the crystal.[17] Hydrogen atoms and counterion have been omitted for
clarity. Displacement ellipsoids correspond to 30% probability.
In summary, the first practical and green reductive N-methylation
and alkylation of amines catalyzed by a specific cobalt complex
has been developed. Applying robust carboxylic acids and H2 as
the ideal reductant, this protocol provides a convenient and
efficient method for the synthesis of various secondary and
tertiary amines. Importantly, a variety of naturally abundant fatty
acids, for instance, caprylic acid, lauric acid and stearic acid can
be successfully applied in this protocol, which also tolerates
other reducible functional groups, such as halogen, alkene, ester
and amide. In comparison to previously known ruthenium-
catalyzed reductive alkylations, cobalt in combination with a
tailor-made triphos ligand enabled the process to proceed under
milder conditions and does not require sensitive additives. This
also provides the basis for highly selective mono-alkylations.
Scheme 5. Mechanistic findings.
Based on the above studies, we postulate the aldimine as a
central intermediate in the major pathway of this reductive
alkylation. Here, the carboxylic acid is reduced to the aldehyde
(or the corresponding aminal), which subsequently forms the
alkylated amine. In addition, reversible reduction to the alcohol
might take place,[10] and at this point amide formation followed
by reduction might exist as minor pathways (Scheme 6). To
identify the probable active catalytic species, the cobalt
Acknowledgements
We thank the analytic department (LIKAT) for their support, the
State of Mecklenburg-Western Pomerania, the Federal State of
Germany (BMBF), and the EU (Grant 670986) for financial
support. We also thank Florian Scharnagl (LIKAT) for providing
L3 and L4, Dr. Jiawang Liu (LIKAT) for helpful discussion as
well as Bianca Wendt (LIKAT) for general assistance.
.
precursor Co(BF4)2 6H2O, triphos(p-anisole) and acetic acid were
mixed in a 1:2:1 ratio and stirred at 100 °C for 3 h under argon.
Indeed, [Co(triphos(p-anisole))OAc]+ catalyst prototype is detected
by ESI-MS analysis at m/z = 922 and its structure could be
unambiguously characterized by single crystal X-ray diffraction
study upon counterion exchange (Figure 3). It is worthy to
Keywords: alkylation • cobalt • homogeneous catalysis •
hydrogenation • tailor-made triphos
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The efficiency of hydrogenative N-
alkylation of amines with readily
available carboxylic acid and H2 could
be dramatically improved using for the
first time cobalt complexes of tailor-
made triphos ligands.
Weiping Liu, Basudev Sahoo, Anke
Spannenberg, Kathrin Junge, and
Matthias Beller*
Page No. – Page No.
Tailored
Cobalt-Catalysts
for
Reductive Alkylation of Anilines with
Carboxylic
Conditions
Acids
under
Mild
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