Sequential hydroaminomethylation/Pd-catalyzed hydrogenolysis as an atom efficient route to valuable primary and secondary amines

Article abstract of DOI:10.1016/j.tetlet.2021.153018

The facile synthesis of valuable primary and secondary amines is reported using a sequential procedure of hydroaminomethylation and Pd-catalyzed hydrogenolysis. The hydroaminomethylation reaction was catalyzed by a cationic Rh(I) iminopyridyl complex and the N-alkylated benzylamines were produced with high chemoselectivity, albeit as mixtures of linear and branched products. Performing the hydrogenolysis reaction using 10% Pd/C, provided access to valuable primary and secondary amines which have applications in the surfactant, pharmaceutical and polymer industries.

Full text of DOI:10.1016/j.tetlet.2021.153018

Tetrahedron Letters 70 (2021) 153018
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sequential hydroaminomethylation/Pd-catalyzed hydrogenolysis as an
atom efficient route to valuable primary and secondary amines
⇑
Jacquin October, Selwyn F. Mapolie
DST-NRF Centre of Excellence in Catalysis (c*-change), Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, Matieland, 7602, Stellenbosch,
South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
The facile synthesis of valuable primary and secondary amines is reported using a sequential procedure of
hydroaminomethylation and Pd-catalyzed hydrogenolysis. The hydroaminomethylation reaction was
catalyzed by a cationic Rh(I) iminopyridyl complex and the N-alkylated benzylamines were produced
with high chemoselectivity, albeit as mixtures of linear and branched products. Performing the
hydrogenolysis reaction using 10% Pd/C, provided access to valuable primary and secondary amines
which have applications in the surfactant, pharmaceutical and polymer industries.
Received 13 November 2020
Revised 13 March 2021
Accepted 17 March 2021
Available online 26 March 2021
Keywords:
Ó 2021 Elsevier Ltd. All rights reserved.
Iminopyridyl complexes
Hydroaminomethylation
Hydrogenolysis
Sequential synthesis
Fatty amines
Amino alcohol
Introduction
[13]. Benzylamine is a masked form of ammonia and its deriva-
tives can undergo debenzylation via Pd-catalyzed hydrogenolysis
Amines are valuable compounds in the pharmaceutical [1], cos-
metic [2] and surfactant industries [3]. Generally, amines are syn-
thesized via the reduction of unsaturated nitrogen-containing
compounds [4] or using processes such as Gabriel synthesis [5],
Hofmann rearrangement [6] and Curtius rearrangement [7]. In
addition, the direct alkylation of ammonia, as well as primary
and secondary amines are also commonly used [8]. These
processes generate stoichiometric amounts of waste and utilize
corrosive acids and bases, while reduction reactions utilize strong
reducing agents (e.g. LiAlH4). Therefore, more environmentally-
friendly processes are required to synthesize these amines. These
processes include catalytic nucleophilic substitution of alcohols
using ammonia [9], reductive amination of carbonyl containing
compounds [10], hydroamination [11] and hydroaminomethyla-
tion [12].
providing access to primary or secondary amines in a facile
manner.
Vorholt and co-workers previously demonstrated the synthesis
of primary amines via an orthogonal tandem amination reaction
[14].
This
entailed
an
initial
rhodium-catalyzed
hydroaminomethylation reaction to produce secondary amines,
which was then followed by cleavage to primary amines using a
ruthenium catalyst in the presence of ammonia.
To the best of our knowledge, the combination of
hydroaminomethylation and hydrogenolysis, for the synthesis of
primary and secondary amines has not been reported. Herein, we
report the synthesis of primary and secondary amines using a com-
bination of hydroaminomethylation and Pd-catalyzed debenzyla-
tion. The production of selected amines which are useful in the
pharmaceutical, polymer and surfactant industries are reported
to illustrate the scope of this methodology.
Hydroaminomethylation, a one-pot tandem reaction combining
hydroformylation with reductive amination, is a versatile reaction
to produce various amines from relatively inexpensive alkene
feedstocks [12]. We have previously demonstrated the
hydroaminomethylation of 1-octene with piperidine, aniline and
benzylamine, catalyzed by imino-pyridine rhodium catalysts
Results and discussion
The hydroaminomethylation of alkenes in the presence of
benzylamine is shown in Scheme 1. This reaction is catalyzed by
C1, a cationic imino-pyridine rhodium complex, the synthesis
and characterization of which was reported previously. This
complex was found to be an efficient catalyst precursor for the
⇑
Corresponding author.
E-mail address: smapolie@sun.ac.za (S.F. Mapolie).
https://doi.org/10.1016/j.tetlet.2021.153018
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

J. October and S.F. Mapolie
Tetrahedron Letters 70 (2021) 153018
Scheme 1. General scheme for the synthesis of amines via hydroaminomethylation and hydrogenolysis.
hydroaminomethylation reaction, producing N-alkyl benzylamines
chemoselectively, albeit with moderate regioselectivities [13].
Attempts to identify the active species was unfortunately not suc-
cessful. In trying to probe the nature of possible reaction interme-
diates, the catalyst precursor was reacted with CO. This revealed
the displacement of the COD ligand by CO to form a dicarbonyl
species which was confirmed by solution IR spectroscopy
(Fig. S46). Attempts to confirm the formation of the Rh-H active
species using high pressure NMR spectroscopy was unfortunately
unsuccessful. No signal was detected in the hydride region of the
1H NMR spectrum when the catalyst precursor was reacted with
syngas in a high pressure NMR tube (Fig. S47).
Given the ability of C1 to mediate the hydroaminomethylation
of simple alkenes, we employed the same catalyst in the
hydroaminomethylation of a wider range of alkenes using benzy-
lamine as the amine substrate. The secondary and tertiary N-sub-
stituted benzylamines produced were then subjected to
hydrogenolysis using 10% Pd/C in the presence of hydrogen
(5 bar) leading to debenzylation to form primary and secondary
amines. The scope of the alkene substrates employed is illustrated
in Table 1. In addition to simple aliphatic alkenes, we also explored
the use of cyclic and aromatic alkenes, as well as alkenes contain-
ing ester and alcohol functionalities.
In most cases, the hydroaminomethylation step produces mix-
tures of secondary and tertiary N-alkylbenzylamines (Scheme 1).
In all cases the alkene conversion is almost quantitative and the
total product yield is high. The yields of the hydroaminomethyla-
tion products, which largely consisted of secondary amines were
based on the amount of starting alkene. The yields of the
Pd-catalyzed debenzylation products were based on the secondary
N-alkylbenzylamine being the principal component.
Unfortunately significant challenges were encountered in trying
to establish the regioselectivity of the hydroaminomethylation
reaction. In the reactions investigated, complex mixtures of sec-
ondary and tertiary N-alkylbenzylamines were obtained during
the hydroaminomethylation process (Scheme 1). In addition to
this, isomerization of the alkene substrate occurs during the initial
stages of the reaction, resulting in the hydroformylation step
involving both 1-alkenes as well as internal alkenes as actual sub-
strates. This leads to complex mixtures of regio-isomers for the
hydroformylation products. For instance, using 1-octene as a sub-
strate can lead to four different hydroformylation products (one
linear and three branched). In the case of longer chain alkenes,
such as 1-dodecene and 1-hexadecene, even more complex mix-
tures are possible since the extent of alkene isomerization is
higher. The situation is further complicated in the case of the ter-
tiary N-alkyl benzylamines which are produced in the
hydroaminomethylation step. The alkyl substituents on the nitro-
gen atom, in addition to the benzyl group, can consist of different
combinations. Thus, it is possible to have two linear alkyl chains,
two branched chains or a mixture of a linear and branched chains.
Even if the components can be separated, which in itself is extre-
mely difficult, the lack of authentic standards for most of the reac-
tion intermediates and products makes it near impossible to
determine the regioselectivity quantitatively. The same complexity
exists when considering the products of the Pd-catalyzed debenzy-
lation reaction where complex mixtures of secondary and primary
amines are obtained.
Hydroaminomethylation of the alkenes with benzylamine was
evaluated using equimolar amounts of the two reagents, since
we initially targeted the primary amines. Given the high activity
of this catalyst in the hydroaminomethylation of 1-octene with
benzylamine, we expanded the reaction scope to also include 1-
dodecene and 1-hexadecene, under the reaction conditions that
we previously reported for the hydroaminomethylation of
1-octene with benzylamine (50 bar CO:H2 (1:3), 85 °C) [13]. How-
ever, the reaction time was extended to 6 h in order to ensure full
conversion of all substrates. This produced the corresponding
N-alkyl benzylamines (as a mixture of secondary and tertiary ami-
nes) in good to excellent isolated yields (1a-3a, 76–98%). The
hydroaminomethylation of 1-dodecene has previously been inves-
tigated by Khan and Bhanage using a Rh-phosphinite catalyst sys-
tem, where full conversion of 1-dodecene with 99%
chemoselectivity towards the amines was obtained [15]. This
was achieved under milder reaction conditions (Rh:1-dodecene
1:2500, 30 bar CO:H2 (7:23), 80 °C, 6 h) compared to those
2

J. October and S.F. Mapolie
Tetrahedron Letters 70 (2021) 153018
Table 1
Synthesis of amines via hydroaminomethylation and hydrogenolysis.
Hydroaminomethylation conditions: alkene:amine (1:1), CO:H2 (1:3, 50 bar), C1 (0.5 mol%), toluene (5 mL), 85 °C, 6 h. Isolated yields.
Hydrogenolysis conditions: 10% Pd/C, EtOH (10 mL), 75 °C, 24 h. Isolated yields.
employed by us. However, it should be noted that in their case, a
secondary amine (di-n-pentylamine) was employed, which are
known to be more reactive than primary amines. To the best of
our knowledge, the hydroaminomethylation of 1-hexadecene in
the presence of syngas has not been previously reported. However,
The alkene substrates can initially undergo isomerization, which
leads to the formation of branched amines (only the linear
products are shown in Fig. 1). 1H NMR spectroscopy and mass
spectrometry revealed that in the case of 1-octene, mostly the
secondary amine (di-nonyl amine, 1b) was formed as a result of
bis-hydroaminomethylation, while in the case of 1-dodecene and
1-hexadecene, products 2b and 3b consisted of complex mixtures
of primary and secondary amines (primary amines were the major
product according to mass spectrometry). In these two cases, the
longer alkyl chains most likely inhibit the second
hydroaminomethylation reaction from taking place, while the
lower reactivity of 1-dodecene and 1-hexadecene in the hydro-
Karakhanov
and
co-workers
[16]
have
studied
the
hydroaminomethylation of 1-hexadecene with dimethylamine in
the presence of methylformate as a syngas surrogate using the
Ru carbonyl complex Ru3(CO)12 as a catalyst precursor.
Hydrogenolysis of the N-alkyl benzylamines produced in the
hydroaminomethylation step provided access to various fatty ami-
nes (Fig. 1), which were isolated in good yields (1b-3b, 73–84%).
Fig. 1. Fatty amines synthesized via hydroaminomethylation and hydrogenolysis.
3

J. October and S.F. Mapolie
Tetrahedron Letters 70 (2021) 153018
formylation step could also negatively impact the overall yield.
Unfortunately, separation of the primary and secondary amines
is a difficult process and we were unable to assess the selectivity
of the reaction.
These fatty amines are important in industry with applications
as lubricants, surfactants and corrosion inhibitors, to name just a
few. In industry fatty amines are normally synthesized via the
Nitrile process using naturally occurring fatty acids [17]. This pro-
cess occurs at high temperatures (>250 °C) and usually requires
long reaction times. Although our approach utilizes rhodium cata-
lysts, it provides access to these amines under relatively mild
conditions.
The hydroaminomethylation of a cyclic alkene, viz. cyclohexene,
with benzylamine gave the corresponding N-di-cyclohexyl benzy-
lamine 4a in 99% yield. Similar results (94% yield) were previously
obtained by Khan and co-workers for the hydroaminomethylation
of cyclohexene with morpholine as an amine source, using a rho-
dium polyether diphosphinite complex [18]. Although their reac-
tion was performed at lower pressures in comparison to our
approach (~28 bar), higher temperatures were used (100 °C) in
combination with a more reactive secondary amine [18].
1-Cyclohexyl-N-(cyclohexylmethyl)methanamine 4b was also
synthesized in good yield (77%) via the debenzylation of 4a. This
amine has found use in the synthesis of rotaxanes which are com-
monly used in the production of molecular motors as well as ultra-
stable dyes [19–21]. This compound is typically synthesized via the
hydrogenation of cyclohexanecarbonitrile (70% conversion), as
reported by Wang and co-workers [22]. However, our approach
is more facile and uses cyclohexene as a less expensive substrate.
The hydroaminomethylation of aryl-based alkenes can provide
access to pharmacologically-active amines, examples of which
are shown in Fig. 2.
Subsequent debenzylation of 5a provided 5b in 41% yield, which
was also obtained as a complex mixture of primary and secondary
amines. Once again as previously mentioned, we were not able to
determine the selectivity for the primary and secondary amines.
Synthesis of the primary amine was previously demonstrated by
the groups of Beller, Ohkuma, and Togo [24–26]. In these reports,
the primary amine was isolated in high yields by both Beller [24]
and Ohkuma [25] (99% and 87%, respectively) using direct methods
in which the corresponding nitrile and azides were employed as
substrates, respectively. In our case, the synthesis of 5b was
achieved via hydroaminomethylation using styrene, followed by
hydrogenolysis. In contrast to our one-pot protocol, Togo and co-
workers [26] obtained primary amine 5b in high yield (~83%) over
multiple synthetic steps, which involved conversion of 4-
phenylbutanoic acid to the corresponding N-alkylsuccinimide over
three steps, followed by deprotection of the protected amine using
hydrazine. The corresponding secondary amine is commonly syn-
thesized via the hydrogenation of cinnamonitrile which also
requires prior synthesis [27].
Given the success in converting the aforementioned alkene sub-
strates into amino-functionalized products, we further examined
the substrate scope by employing hydroxy and methoxy
containing aryl alkenes. For example, eugenol underwent
bis-hydroaminomethylation with benzylamine, forming the corre-
sponding amine (6a) (only the linear products are shown in Fig. 2)
in high yield (93%). Debenzylation of 6a gave 6b in 94% yield as a
complex mixture of linear and branched isomers.
Estragole was also successfully converted to the corresponding
product 7a in good yield (77%) as a complex mixture of secondary
and tertiary N-alkylbenzylamines. Similar yields were previously
obtained by Gusevskaya and co-workers [28] for the
hydroaminomethylation of estragole with di-n-butylamine (75%),
albeit at a slightly higher pressure (60 bar) and using a longer reac-
tion times (24 h), making our system better in this regard. Subse-
quent debenzylation of 7a gave 7b as a complex mixture of
primary and secondary amines. The primary amine is a tyra-
mine-analogue and this approach represents an improvement on
the previously reported synthetic approaches for this compound
[29].
In this regard, the hydroaminomethylation of styrene produced
5a in 93% yield as a complex mixture of linear and branched prod-
ucts (only the linear products are shown in Fig. 2) and as a complex
mixture of secondary and tertiary N-alkyl benzylamines. As previ-
ously mentioned, this makes determining the regioselectivity very
challenging.
This yield is superior to that obtained by Zhang and co-workers
(54%) in their study of the hydroaminomethylation of styrene with
We further studied the hydroaminomethylation of ester and
alcohol functionalized alkenes, such as methyl 10-undecenoate
and pent-4-en-1-ol to produce ester and alcohol containing amines
(Fig. 3).
benzylamine, using
a rhodium tetraphosphine-based catalyst
system [23]. In addition to this, they used a higher reaction
temperature of 125 °C and a longer reaction time of 16 h.
Methyl 10-undecenoate, a bio-renewable substrate derived
from castor oil, was converted into the corresponding amine 8a
in 99% yield via hydroaminomethylation. This yield is superior to
that obtained by Vorholt and co-workers for the
hydroaminomethylation of methyl 10-undecenoate (70%) [30].
However, in their case the reaction was performed with piperazine,
which undergoes bis-hydroaminomethylation. In our system, the
hydrogenolysis of 8a produced 8b (complex mixture of linear
and branched products), an
a,x-diester, in 77% yield. This com-
Fig. 2. Aryl-based primary and secondary amines synthesized via
Fig. 3.
a,x-Diester and amino-alcohol synthesized via hydroaminomethylation and
hydroaminomethylation and hydrogenolysis.
hydrogenolysis.
4

J. October and S.F. Mapolie
Tetrahedron Letters 70 (2021) 153018
pound can potentially be used in the synthesis of polyamide poly-
mers, resembling well-known Nylon-type polymers [31].
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Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153018.
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