Manganese-Catalyzed Multicomponent Synthesis of Tetrasubstituted Propargylamines: System Development and Theoretical Study

Article abstract of DOI:10.1002/adsc.202000566

Herein, we report a catalytic system based on the earth-abundant manganese for the ketone, amine, alkyne (KA²) reaction. The efficiency of manganese manifests at relatively high temperatures, combined with sustainable reaction conditions, and provides a tool for accessing propargylamines from structurally diverse starting materials, including synthetically relevant and bioactive molecules. Our efforts were also aimed at shedding light on the catalytic mode of action of manganese in this transformation, in order to explain its temperature-related behavior. The use of computational methods reveals mechanistic aspects of this reaction indicating important points regarding the reactivity of both manganese and ketones. (Figure presented.).

Full text of DOI:10.1002/adsc.202000566

Title: Manganese-Catalyzed Multicomponent Synthesis of
Tetrasubstituted Propargylamines: System Development and
Theoretical Study
Authors: Stavros Neofotistos, Nikolaos Tzouras, Martin Pauze, Enrique
Gómez-Bengoa, and Georgios Vougioukalakis
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000566
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10.1002/adsc.202000566
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.202
Manganese-Catalyzed
Multicomponent
Synthesis
of
Tetrasubstituted Propargylamines: System Development and
Theoretical Study
Stavros P. Neofotistos,a Nikolaos V. Tzouras,a Martin Pauze,b Enrique Gómez-
Bengoa,b and Georgios C. Vougioukalakis*a
a
S. P. Neofotistos, N. V. Tzouras, Prof. Dr. G. C. Vougioukalakis
Department of Chemistry, Laboratory of Organic Chemistry
National and Kapodistrian University of Athens
Panepistimiopolis, 15771 Athens, Greece
E-mail: vougiouk@chem.uoa.gr
Tel: +30-210-7274230
Fax: +30-210-7274761
Martin Pauze, Prof. Dr. E. Gómez-Bengoa
b
Department of Organic Chemistry I, Faculty of Chemistry
University of the Basque Country
UPV/EHU, 20018 Donostia-San Sebastián, Spain
Received:
Supporting information for this article containing copies of the 1H and 13C NMR spectra, as well as the Cartesian
coordinates to which the present manuscript refers, is available on the WWW under
http://dx.doi.org/10.1002/adsc.201######.
Abstract. Herein, we report a catalytic system based on the
earth-abundant manganese for the ketone, amine, alkyne
(KA2) reaction. The efficiency of manganese manifests at
relatively high temperatures, combined with sustainable
reaction conditions, and provides a tool for accessing
propargylamines from structurally diverse starting
materials, including synthetically relevant and bioactive
molecules. Our efforts were also aimed at shedding light on
the catalytic mode of action of manganese in this
transformation, in order to explain its temperature-related
behavior. The use of computational methods reveals
mechanistic aspects of this reaction indicating important
points regarding the reactivity of both manganese and
ketones.
Keywords: manganese catalysis; ketone-amine-alkyne
coupling; sustainability; multicomponent reactions; DFT
calculations
chemical transformations, thus fulfilling the
conditions which have been established by the
diversity-oriented synthesis strategy and natural
product synthesis.[1,2,10–17] Moreover, through the
integration of carbon dioxide or other small
Introduction
Propargylamines are a versatile family of organic
compounds that have found numerous applications in
the fields of organic synthesis and pharmaceutical
chemistry.[1,2] The biological activity of various
members of their family renders them inherently
valuable in drug development, mostly against
molecules,
propargylamines
can
serve
as
intermediates or precursors for the synthesis of
various heterocyclic compounds,[1] such as
oxazolidinones,[18,19] same as their propargylic
neurodegenerative
diseases.[1–9]
In
addition,
alcohol
congeners.[20]
Amongst
others,
propargylic amines are useful building blocks in
organic synthesis, providing access to diverse
molecular architectures.[1,2] The unique structure of
these compounds is based on the existence of an
amine group in β-position to an alkyne moiety, which
leads to diverse reactivity.[1] These characteristics
make propargylamines susceptible to a variety of
propargylamines can be accessed in a facile manner
through
catalytic,
multicomponent
reaction
protocols,[1,2,21–25] thus minimizing the required effort,
time, and the generation of waste related to multistep
processes.[26–33]
The development of various catalytic systems, based
on sustainable and biorelevant transition metals,[34] as
1
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10.1002/adsc.202000566
Advanced Synthesis & Catalysis
well as the ever increasing interest related to atom-
and step-economy arising from multicomponent
synthesis combined with C-H activation,[35] allows
the discovery of novel and green methodologies.[26–33]
The A3 coupling (aldehyde, amine, alkyne) is a well-
known example of such a methodology.[2,36,37]
Various sustainable and highly efficient catalytic
protocols have been employed for the synthesis of
trisubstituted propargylamines based on this
multicomponent coupling.[36–45] Remarkably, not long
after the initial discovery of this reaction,
enantioselective versions were also developed,
utilizing chiral ligands.[2b,46,47]
prochiral, linear ketones as coupling partners.[66]
Likewise, a Cu(I) based system developed by Ma and
co-workers was also very efficient for the KA2
coupling of secondary amines, various ketones and
terminal alkynes, in toluene, along with molecular
sieves to assist with water removal.[67] The same
research group was the first to report the successful
integration of aromatic ketones, in the KA2 coupling,
which was mediated by a catalytic system based on
CuBr2, along with the use of Ti(OEt)4 and sodium
ascorbate.[68] Naturally, the increasing interest in this
reaction and its potential has led to the development
of a multitude of heterogeneous catalytic systems.
Some leading examples include the use of Cu2O
nanoparticles on titania,[69] nano Cu2O-ZnO,[70]
Cu2O/nano-CuFe2O4,[71] CuO/Fe2O3 nanoparticles,[72]
Cu(II)-hydromagnesite,[73] polystyrene-supported, N-
phenylpiperazine-CuBr2, and highly active, polymer-
supported bipyridine-CuBr2,[74] Cu(II)@furfural
imine-decorated Halloysite,[75] CuI on Amberlyst A-
21,[76] as well as semi-heterogeneous, magnetically
Ketimines exhibit lower reactivity than aldimines, a
fact that stems from both their stereochemical and
electronic features.[48,49] Nucleophilic addition to
ketimines is in general challenging, although
ketimines obtained from cyclohexanone are relatively
reactive, due to the release of torsional strain.[50–52]
Along these lines, employing ketones instead of
aldehydes in the A3 coupling remained a challenge
until almost a decade ago. The synthesis of ketone-
derived, tetrasubstituted propargylamines, through a
catalytic, multicomponent coupling strategy, was
attempted by several research teams, considering the
great abundance of different natural products that
possess α-tertiary amine moieties,[53] along with the
inherent value of propargylamines and the scarcity of
synthetic strategies leading to such molecular
scaffolds.[54–57] An early related example was
demonstrated by Ramón and co-workers in 2010,
when the desired product was obtained in 38% yield
after 7 days of reaction between piperidine, 3-
pentanone, and phenylacetylene, catalyzed by
Cu(OH)x-Fe3O4 as the catalyst.[58] Nonetheless, the
first breakthrough was made when the research group
of Van der Eycken successfully prepared various
tetrasubstituted propargylamines, derived from
cyclohexanones, benzylamines and phenylacetylene,
using a homogeneous, CuI-based and microwave-
assisted catalytic system, under neat conditions. This
discovery was made possible by taking advantage of
the high reactivity of cyclohexanones, whilst they
named the reaction “KA2 coupling” (ketone, amine,
alkyne – Scheme 1).[59] In a later work, the same
research group utilized azoles instead of alkynes,
along with secondary amines and cyclic ketones,
[77]
recoverable graphene oxide-supported CuCl2.
Catalytic systems based on other metals have been
also developed, such as Ag-doped nanomagnetic γ-
Fe2O3@DA
core-shell
hollow
hollow
spheres,[79]
N-heterocyclic
spheres,[78]
Fe2O3@SiO2‐ IL/Ag
polystyrene-supported
Au(III).[80]
and
carbene-
More recently, our research group reported a robust
catalytic system for the KA2 reaction, introducing
Zn(OAc)2 as
a
reliable catalyst under neat
conditions.[81] Additionally, we found that a catalytic
system based on ZnI2 can mediate the tandem
formation of allenes from the in situ generated
propargylamines in a one-pot procedure. This work
highlighted that there is substantial reason to
investigate new metals in this reaction, in order to
gain more insight into its underlying principles, and,
more importantly, that the choice of reaction
conditions can lead to new and/or improved reactivity.
under
a
similar, copper-catalyzed/microwave-
irradiated protocol.[60] A catalytic system based on
AuBr3 in 4.0 mol% loading was also developed,
using for the most part secondary amines,
cyclohexanones, and phenylacetylene.[61] In a similar
manner, a homogeneous N-heterocyclic carbene-
Au(I)-based protocol was employed towards
polysubstituted dihydropyrazoles via
a
three-
component annulation of alkynes with N, N΄-
disubstituted hydrazines and aldehydes/ketones.[62]
Larsen and co-workers developed additional efficient
systems for the KA2 coupling, based on CuCl2 or
Cu(OTf)2.[63-65] Further expansion of the scope of the
reaction was achieved when Ti(OEt)4 was employed
as an additive, thereby allowing the integration of
Scheme 1. The metal-catalyzed KA2 coupling reaction.
Manganese is a particularly attractive metal on
account of its high natural abundance (the 3rd
2
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10.1002/adsc.202000566
Advanced Synthesis & Catalysis
transition metal in the earth’s crust after iron and
titanium) and biocompatibility, which is particularly
valuable for the pharmaceutical industry.[82]
According to a recent report of the European
Medicine Agency, manganese and copper are
considered metals of low safety concern.[83] Therefore,
manganese is a prominent candidate for the mediation
of all kinds of chemical transformations.[82] In this
regard, a plethora of manganese-based homogeneous
catalytic systems have been developed,[82]
successfully catalyzing the hydrosilylation of
carbonylic compounds,[84,85] the electrochemical CO2
reduction,[86–92] as well as the oxidation and allene
epoxidation reactions.[93–99] A well-known example of
manganese catalysis is the Katsuki reaction, which
utilizes a Mn(I)-salen complex for the epoxidation of
allenes.[98] Similarly, Mn(I)-based catalytic protocols
utilizing porphyrin,[93,95,96] phthalocyanine,[97] or
polyamine ligands,[100] have been reported. Mn-
catalyzed C-H activation approaches have been also
developed.[101–105] More specifically, Wang and co-
workers introduced the first manganese-catalyzed
aromatic C−H alkenylation with terminal alkynes.[102]
Exploiting various pyridine derivatives as directing
groups, they successfully accomplished the
alkenylation of aromatic rings, mediated by a
MnBr(CO)5 complex and dicyclohexylamine as the
base, at high chemo-, regio-, and stereo-selectivity.
Interestingly, the same group proposed the formation
of a σ-alkynyl intermediate in the catalytic cycle,
based on Density Functional Theory (DFT)
studies.[102] The formation of a Mn-acetylide was also
proposed by Takai and co-workers as an
intermediate.[106] Specifically, they reported that the
mechanism for the hydantoin synthesis included an
oxidative addition of a terminal alkyne to form an
Mn-acetylide, followed by the insertion of an iso-
cyanate into the manganese–carbon bond of the
manganese acetylide.[106] Given that the formation of
Mn-acetylides had been well established, a novel,
MnCl2-based protocol for the mediation of the A3
coupling, along with a tandem intramolecular [3 + 2]
dipolar cycloaddition, was reported by Lee and co-
workers, introducing an efficient, one-pot strategy for
the synthesis of propargylamines, as well as fused
triazoles.[107]
opportunity to study the reaction mechanism using
computational tools for the first time, in order to
further understand and more accurately pinpoint the
reasons why ketone functionalization is significantly
more challenging than that of aldehydes.
Results and Discussion
Based on our experience with the zinc-based catalytic
protocol we have recently developed,[81] we chose
cyclohexanone
(1a),
piperidine
(2a)
and
phenylacetylene (3a) as model substrates for the
optimization of the novel, manganese-based catalytic
system. When Mn(OAc)2 was employed in 20 mol%
loading and the reaction was carried out under neat,
inert conditions at 120 oC for 20 hours,
propargylamine 4a was obtained in 21% GC yield
(Entry 1, Table 1). Despite this result, proving that
manganese is able to mediate this reaction, a
substantial amount of by-products were detected by
GC/MS analysis.[20] Repetition of the reaction in
o
toluene (1 M) at 120 C, resulted in a 12% GC yield,
which is considerably lower than the neat conditions
(Entry 2, Table 1). This was a first indication that the
reaction is favored under neat conditions. Then, we
decided to proceed with the study of manganese
halides. MnF2 in 20 mol% loading under inert, neat
o
conditions at 120 C for 20 hours, resulted in a 52%
yield (Entry 3, Table 1). When the same reaction was
performed in toluene (1 M), the product was obtained
with only 8% yield (Entry 4, Table 1). A significant
increase in the reaction yield was observed, under
o
neat conditions, at 120 C using MnCl2 as a catalyst,
resulting in a 58% isolated yield (Entry 5, Table 1),
suggesting that the counter ions of the manganese
catalyst have a significant impact on the reaction.
When the same reaction was performed in toluene (1
M), it resulted in an 18% GC yield (Entry 6, Table 1).
When MnBr2 was employed in 20 mol% loading at
o
120 C, under neat, inert conditions, the desired
product was obtained in 74% isolated yield (Entry 7,
Table 1). Importantly, the formation of side products
was also significantly reduced. The same reaction,
when performed in toluene (1 M), resulted in the
desired propargylamine 4a in 45% GC yield (Entry 8,
Table 1). When MnI2 was used in 20 mol% loading at
To the best of our knowledge, manganese catalysis
has not yet been tested in the KA2 coupling. Inspired
by the applications of sustainable metal catalysis in
green organic transformations,[35,108–111] as well as our
recent work on zinc catalysis,[81] we became
interested in studying the potential of manganese
catalysis in the KA2 reaction. Our primary goal was
the development of a highly-efficient, green, and
user-friendly catalytic system based on a widely-
available and cost-efficient manganese source, which
could mediate the KA2 coupling reaction of various
challenging and synthetically intriguing substrates,
under solvent-free conditions. Ideally, our KA2
coupling protocol would be also viable under air,
improving the sustainable aspects of this
transformation even further. Finally, this provided an
o
120 C, under neat, inert conditions, the desired
product was obtained in 55% GC yield (Entry 9,
Table 1). Besides being very difficult to handle
because of its hydroscopic nature, MnI2 is also
characterized by reduced solubility in the reaction
mixture. Therefore, the same reaction was performed
in toluene, which efficiently dissolves MnI2,
affording propargylamine 4a in 79% GC yield (Entry
10, Table 1). Furthermore, a blank test, using only
molecular sieves, was performed, but, as anticipated,
the product was not observed, as judged by GC-MS
analysis (Entry 11, Table 1). Based on the above
results, we decided that the best manganese source is
MnBr2, as it is easy to handle and it also affords very
high product yields. The use of molecular sieves was
3
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10.1002/adsc.202000566
Advanced Synthesis & Catalysis
sieves
deemed unnecessary, since their use only increased
the complexity of the protocol (vide infra), while the
use of solvent under these conditions negatively
affects the reaction outcome. More importantly, the
employment of solvent-free conditions is in line with
the principles of green chemistry.
2
3
Mn(OAc)2 20
Toluene (1M) 12
MnF2
20
Neat & m.
sieves
52
4
5
MnF2
20
20
Toluene (1M)
8
Then, we tested our protocol at various temperatures,
using MnBr2 at 20 mol% loading under an inert
atmosphere and neat conditions for 20 hours. At 80
oC, the product was formed in 14% GC yield (Entry 1,
MnCl2
Neat & m.
sieves
63 (58)
6
7
MnCl2
MnBr2
20
20
Toluene (1M) 18
o
Table 2). Performing the same reaction at 100 C
Neat & m.
sieves
78 (74)
allowed the formation of propargylamine 4a in 44%
GC yield. When the reaction was repeated under the
o
same conditions at 120 C, it led to the formation of
8
9
MnBr2
MnI2
20
20
Toluene (1M) 45
the desired product in 77% GC yield (Entry 3, Table
2). This result also suggested that the use of
molecular sieves is not necessary, given that the
results are practically the same with or without their
presence (compare Entry 3, Table 2 with Entry 7,
Table 1). When we performed the reaction employing
MnBr2 at 20 mol% loading under inert atmosphere
Neat & m.
sieves
55
10
11
MnI2
-
20
-
Toluene (1M) 79
Neat & m.
sieves
Traces
o
All reactions were performed on a 2.0 mmol scale, running
at 120 ℃ for 20 hours. Yield determined by GC/MS
analysis, using n-octane as the internal standard. After
and solvent-free conditions at 130 C for 20 hours,
a)
the product was formed in 99% GC yield and 94%
isolated yield (Entry 4, Table 2). Expanding our
investigation, the same reaction was performed in the
presence of molecular sieves, giving exactly the same
results (Entry 5, Table 2), reaffirming the
needlessness of molecular sieves.
b)
column chromatography.
Table 2. Optimization studies.
We were also interested in shedding some light on the
mechanism of the reaction. Besides carrying out a
series of theoretical calculations (vide infra), we
performed the transformation using MnBr2, under the
thus far optimal conditions (Entry 6, Table 2), by also
adding
2.0
equivalents
of
(2,2,6,6-
Entry mol%
Temp.
Additive % GC yield a)
(isol. yield) b)
(℃)
tetramethylpiperidin-1-yl)oxidanyl (TEMPO), a well-
known free radical scavenger. Again, the product was
formed in 98% GC yield. This suggests that the
catalytic mechanism does not involve radical
intermediates.
Finally, we investigated the impact of the catalyst
loading on the reaction outcome (Entries 7-9, Table
2). To our surprise, the reaction can be very
efficiently carried out even at 5 mol% MnBr2 (Entry
9, Table 2) affording the desired product in 98% GC
yield and 95% isolated yield. This very low catalyst
loading, along with the solvent-free conditions, the
sustainable nature of Mn, and the fact that this is a
multicomponent reaction, render this protocol highly
appealing and “green”.
1
2
3
4
5
6
20
20
20
20
20
20
80
-
-
-
-
14
100
120
130
130
130
40
77
99 (94)
m. sieves 99
TEMPO
(2eq)
98
7
8
9
20
10
5
130
130
130
-
-
-
99
98
98 (95)
All reactions were performed on a 2.0 mmol scale, with
Table 1. Metal sources screening and solvent tests.
a)
MnBr2, under neat conditions for 20 hours.
Yield
determined by GC/MS analysis, using n-octane as the
internal standard. b) After column chromatography.
For the last part of our investigation we studied the
progress of the reaction over time (Table 1, see
Supporting Information). MnBr2 was used at 5 mol%
Entry Metal
source
mol% Solvent
% GC
yielda)
(isol.
o
loading under an inert atmosphere at 130 C and
solvent-less conditions, while the reaction was
repeated for different reaction times and analysed by
GC/MS. Based on these results, we were able to
yield)b)
1
Mn(OAc)2 20
21
Neat & m.
4
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10.1002/adsc.202000566
Advanced Synthesis & Catalysis
construct a reaction profile plot (Figure 1). The
reaction reaches a yield plateau in 12 hours,
proceeding to completion after 18 to 20 hours. Based
on this result, we decided to run our substrate scope
investigation studies that follow for 20 hours, given
that some of the substrates we were planning to
utilize are considered demanding coupling partners.
impact on the outcome of the reaction, which was not
observed when 4-decanone was deployed.
Surprisingly, our catalytic protocol was also able to
successfully mediate the KA2 coupling reaction of
aromatic ketones. This result is of outmost
importance, since, thus far, only one other example
has been reported in the literature.[68] Specifically, we
screened aromatic ketones bearing both electron-
withdrawing (EWGs) and electron-donating groups
(EDGs). When 4-methoxy-acetophenone was used,
propargylamine 4j was isolated in 34% isolated yield.
Similarly, when 4-chloro-acetetophenone was
employed, the respective propargylamine 4k was
obtained in 42% isolated yield. When benzophenone
was utilized, propargylamine 4l was not observed,
which may be because of the increased steric
hindrance imparted from the two phenyl moieties in
the α-position of the carbonyl group.
Figure 1. Kinetic profile of the reaction.
While investigating the scope of ketones (Scheme 2),
phenylacetylene was used in combination with
primarily pyrrolidine, as well as piperidine (Scheme
2). It was quickly determined that besides
cyclohexanone a variety of different ketones can be
successfully employed in this reaction under our
protocol, with cyclopentanone and piperidine leading
to propargylamine 4b in 67% isolated yield. When
cycloheptanone was used, propargylamine 4c was
obtained in 73% yield. Propargylamines 4d or 4e
were obtained, in 75 or 91% isolated yield,
respectively, when cyclopentanone or cyclohexanone
were used along with pyrrolidine. The respective
propargylamine 4f, stemming from cyclohexane-1,2-
dione, was not obtained. A drop in the yield was
observed when linear ketones were employed. More
specifically, 2-pentanone and 3-pentanone resulted in
propargylamines 4g and 4h in 38% and 48% isolated
yields, respectively. On the contrary, when 4-
decanone was used, propargylamine 4i was obtained
in 68% isolated yield. The increased steric hindrance
and the lack of torsional strain release during the
acetylide attack on the in-situ formed ketiminium ion
are most probably the reasons for this reactivity
pattern.[50–52,64] Additionally, the lower boiling points
of 2-pentanone and 3-pentanone may have a negative
Scheme 2. The manganese-catalyzed KA2 coupling: Scope
of ketones. All reactions were performed on a 2.0 mmol
scale and isolated yields are reported in parentheses. a) The
desired product was not observed by GC/MS analysis.
To study the scope of alkynes (Scheme 3),
cyclohexanone, along with piperidine or pyrrolidine,
were coupled with various terminal alkynes, leading
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000566
Advanced Synthesis & Catalysis
to
the
formation
of
the
corresponding
simple and more elaborate aliphatic alkynes (e.g. 2-
methylbut-3-yn-2-ol) can be derivatized.
propargylamines. The presence of electron-donating
groups (EDGs) on the aromatic ring of the aromatic
terminal alkynes leads to the generation of
propargylamines in high to excellent yields.
Specifically,
cyclohexanone
3-ethynyl-toluene
and piperidine
couples
to
with
afford
propargylamine 4m in 81% isolated yield. Similarly,
when 4-ethynyl-toluene was employed along with
pyrrolidine and cyclohexanone, propargylamine 4n
was isolated in 87% yield. Propargylamine 4o was
obtained in 70% isolated yield when p-methyl-
phenylacetylene along piperidine and cyclohexanone
were used. The coupling between 4-methoxy-2-
methyl-phenylacetylene,
piperidine
and
cyclohexanone led to the synthesis of 4p in 89%
isolated yield. Moreover, propargylamine 4q was
synthesized in 87% isolated yield using p-methoxy-
phenylacetylene along with cyclohexanone and
piperidine. We also became interested in the use of
nornicotine, along with 2-methylbut-3-yn-2-ol and
cyclohexanone, which allowed the synthesis of
product 4r as a single diastereoisomer (see ESI) in
81% isolated yield. Nornicotine is a natural,
biologically-active molecule, bearing a pyridine
moiety on the pyrrolidine heterocycle. Additionally,
the pyrrolidine moiety is especially useful for
derivatization of propargylic amines, taking into
account their role as precursors to allenes.[112,113]
Similarly, 2-methylbut-3-yn-2-ol is a useful handle
for various applications,[114–119] providing access to
terminal alkynes via a variety of deprotection
techniques.[120,121] Alkynes bearing halide-containing
moieties were also tested under our catalytic protocol.
First, 4-chloro-ethynylbenzene was employed, along
with pyrrolidine and cyclohexanone, leading to
propargylamine 4s in 77% isolated yield. When
piperidine was used instead of pyrrolidine, the
desired propargylamine (4t) was isolated in 64%
yield. When 2-bromo-phenylacetylene was coupled
with cyclohexanone and piperidine, the resulting
propargylamine (4u) was obtained in 57% isolated
yield. This decrease in yield may stem from the
increased steric hindrance, because of the presence of
the bromine atom in the ortho position of the
aromatic ring, obstructing the nucleophilic attack of
the manganese acetylide. Additionally, upon using p-
trifluomethyl-phenylacetylene, propargylamine 4v
was observed by GC/MS analysis in low yields, but
its isolation proved extremely difficult. This result
Scheme 3. The manganese-catalyzed KA2 coupling: Scope
of alkynes. All reactions were performed on a 2.0 mmol
scale and isolated yields are reported in parentheses. a) The
1
diastereomeric ratio was determined by H-NMR analysis
b)
(see ESI).
This compound was detected by GC/MS
analysis; however, it decomposed during column
chromatography.
A wide variety of amines was also used, along with
phenylacetylene and cyclohexanone (Scheme 4). As
mentioned above, propargylamine 4a was obtained in
95% isolated yield during the optimization studies of
our catalytic protocol. When morpholine was used,
propargylamine 4x was obtained in 94% isolated
yield, while GC/MS analysis showed complete
conversion. Benzylamine was also found to be a
suitable coupling partner; propargylamine 4y was
obtained in 46% isolated yield. This decreased yield
may be attributed to the increased stability of the
intermediate ketimine. Similarly, when p-methoxy-
benzylamine was used, the resulting propargylamine
4z was isolated in 43% yield. We also tested the
efficiency of our catalytic protocol on aliphatic
suggests
that
strongly
electron-withdrawing
substituents reduce the ability of the corresponding
acetylides to act as effective nucleophilic species.
Furthermore, this observation agrees with the existing
literature, in which the use of highly electron-
deficient alkynes is rarely reported in similar studies,
due to the decreased nucleophilicity of the respective
acetylides.[68] Finally, 1-octyne was successfully
employed, in combination with piperidine and
cyclohexanone, affording propargylamine 4w in 70%
isolated yield. Therefore, under these conditions, both
6
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10.1002/adsc.202000566
Advanced Synthesis & Catalysis
amines. N-octylamine, along with cyclohexanone and
phenylacetylene, furnished propargylamine 4za in
67% isolated yield. Along the same lines, utilization
of cyclohexylamine led to the desired product (4zb)
in 58% yield. Upon using the secondary amine di-n-
propylamine, the desired product 4zc was formed in
61% yield. Interestingly, the coupling between
nornicotine, cyclopentanone and phenylacetylene led
to the formation of the corresponding propargylamine
(4zd) as a single diastereoisomer in 88% isolated
yield, without the need of purification via column
chromatography, since crystallization of the product
was achieved using a simple, green protocol
(described in the experimental section), developed
from our research group in previous studies.[81]
Aromatic amines have not been successfully utilized
in the KA2 coupling reaction thus far. Indeed,
although the product of the coupling reaction of p-
methoxy-aniline (4ze) was observed by GC/MS
analysis, it rapidly decomposes in light and, despite
our efforts, could not be isolated.
We continued by testing our protocol under ambient
conditions, performing the reaction under air. More
specifically, we studied the coupling between
morpholine, phenylacetylene and piperidine, which,
under inert conditions, affords the synthesis of the
desired product (4x) in 94% yield. To our surprise,
our protocol furnished product 4x in 89% isolated
yield under air, after chromatographic purification.
According to GC/MS analysis, the presence of air
only slightly increased the formation of by-products.
Additionally, we performed the synthesis of 4x on
large scale under air, to evaluate the scalability of our
protocol. Upon using 10 mmols of morpholine, along
with equimolar amounts of cyclohexanone and
phenylacetylene, the desired product was obtained in
93% isolated yield.
Scheme 4. The manganese-catalyzed KA2 coupling: Scope
of amines. All reactions were performed on a 2.0 mmol
scale and isolated yields are reported in parentheses. a) The
1
diastereomeric ratio was determined by H-NMR analysis
b)
(see Supporting Information).
The compound was
detected by GC/MS analysis; however, it decomposes
rapidly under ambient light. Despite our efforts, we could
not isolate and characterize it.
To gain some insight into the reaction mechanism, we
carried out DFT calculations with the Gaussian 16 set
of programs, using the B97-D functional for the
structure optimizations, together with the 6-31G(d,p)
basis sets for all the atoms. Experimentally, the
reactions are run in neat conditions, and we used
cyclohexanone in an implicit solvent model
(IEFPCM) for the best description of the reaction
medium during the energy refinements. We wanted to
get information particularly about the role of the
manganese salts during the process and also about the
high temperatures needed in the reaction. As reagent
models for the calculations, we used MnBr2,
cyclohexanone
(1a),
piperidine
(2a)
and
phenylacetylene (3a).
The first interesting data is that the manganese
dibromide and its complexes with the substrates have
lower energy in the quartet spin state than in the
doublet for every computed structure (usually > 10
kcal/mol difference), showing that the metal contains
three unpaired electrons in degenerate orbitals, along
the entire reaction coordinate. Initially, the
coordination of MnBr2 to the triple bond in I
increases the acidity of the alkyne, and activates it for
7
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10.1002/adsc.202000566
Advanced Synthesis & Catalysis
the deprotonation by piperidine.[122] Upon proton
abstraction, slippage of the metal fragment from the
π-coordination to the terminal position produces the
ate complex II, which is 4.2 kcal/mol higher in
energy than I (Scheme 5a). Therefore, the reactive
species II must be in a small concentration in the
reaction medium. Then, the attack of the alkynyl-
manganese II species to the iminium electrophile III
presents an affordable activation energy (23.9
kcal/mol), in a transition state (TS1, Scheme 5b) that
does not present any interaction between the
manganese and the iminium moiety. After the final
product is formed, a stable complex IV was located,
containing the expected N-Mn coordination. Taken
both steps together (from I to TS1), the overall
activation energy is 28.1 kcal/mol, which is in
agreement with the high temperatures needed in the
process. In other words, the nucleophilic attack of II
to III could be moderately fast (23.9 kcal/mol), but is
probably unfavourably affected by the small
concentration of the nucleophile in the reaction
medium. As detailed in the experimental section,
MnBr2 proved to be the most efficient catalyst,
followed by MnI2 and MnCl2 (Table 1). Indeed, the
activation energy of TS1 in the presence of MnI2 is
higher (25.7 kcal/mol) than with MnBr2. Meanwhile,
MnCl2 decreases the barrier to 22.8 kcal/mol, but its
lower efficiency seems to be linked to a decreased
coordination energy with the triple bond (>4 kcal/mol
worse than MnBr2), inducing a lower concentration of
II in the reaction medium.
formation by nucleophilic attack of the alkyne to the
iminium cation.
Conclusion
A sustainable catalytic system based on manganese
has been developed for the challenging KA2 coupling.
The efficiency of MnBr2 is reflected on the low
catalyst loading needed and the range of substrates
that can be derivatized. DFT calculations show that
the coordination of MnBr2 activates the alkyne to
facilitate its deprotonation by the amine, forming an
anionic complex, which is nucleophilic enough to
attack the iminium species. The moderate activation
energy of the C-C bond forming process, together
with the low concentration of the alkynyl-manganese
bromide, make this step rate limiting, explaining the
range of temperatures used experimentally. This
result suggests that the reaction rate should increase,
even at lower temperatures, if appropriate ligand
design enables the stabilization of the generated
acetylide species, in order for its concentration to be
higher, and also enhances its nucleophilicity. Further
investigation based on these observations is ongoing
in our laboratories.
Experimental Section
General reagent information
All chemicals were purchased from commercial sources
and were used as received, with the exception of
cyclohexanone and piperidine, which were distilled before
use. All metal sources were in anhydrous form and their
purity grade was at least 98%. Toluene purification was
carried out according to published procedures, and the
solvent was distilled and stored under inert atmosphere
prior to use. The reactions were set up in a fume hood and
allowed to proceed under an atmosphere of argon, in
Teflon seal screw-cap pressure tubes which were flame-
dried prior to use. The course of the reactions was followed
by thin layer chromatography (TLC), using aluminium
sheets (0.2 mm) coated with silica gel 60 with fluorescence
material absorbing at 254 nm (silica gel 60 F254) or by
GC-MS analysis of aliquots. The purification of the
products was carried out by flash column chromatography,
using columns packed with silica gel 60 (230-400 mesh)
and the corresponding eluting system.
Computational Methods
All reported structures were optimized at Density
Functional Theory level by using the unrestricted B97-
D[123] functional, which includes Grimme´s dispersion, as
implemented in Gaussian 16.[124] Optimizations were
carried out with the 6-31G(d,p) basis set taking into
account the doublet and quartet spin states for the Mn-
containing species. The reported energy values correspond
to Gibbs Free energies, including a solvent model
(IEFPCM, cyclohexanone).[125] The critical stationary
points were characterized by frequency calculations in
order to verify that they have the right number of
imaginary frequencies, and the intrinsic reaction
coordinates (IRC)[126] were followed to verify the energy
profiles connecting the key transition structures to the
correct associated local minima.
Scheme 5. a) Deprotonation equilibrium between MnBr2-
activated alkyne and alkynyl-Mn complex. b) C-C bond
General analytical information
8
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10.1002/adsc.202000566
Advanced Synthesis & Catalysis
1H, 13C and 19F NMR spectra were measured on a Varian
Mercury 200 MHz, or a Brucker Avance 400 MHz
instrument, using CDCl3 as the solvent and its residual
A Teflon seal screw-cap pressure tube equipped with a
stirring bar was charged with 5 mol% MnBr2 (21.5 mg, 0.1
mmol). Under air, 2.0 mmol of morpholine (174 mg, 175
μL) were added and the mixture was stirred until the solid
was partially dissolved. 2.0 mmol of phenylacetylene (204
mg, 220 μL) were added and the mixture was stirred at
room temperature until the solid was completely dissolved.
Afterwards, 2.0 mmol of cyclohexanone (196 mg, 207 μL)
were added and the pressure tube was quickly sealed by a
Teflon seal screw-cap. The reaction mixture was stirred in
an oil bath in an oil bath, preheated at 130 oC, for 20 hours.
After allowing the mixture to cool to room temperature,
ethyl acetate was added and the mixture was stirred rapidly
for 5 minutes. The crude product was filtered through a
short silica gel plug using 5.0 mL of ethyl acetate. The
mixture was concentrated under vacuum, and loaded atop a
silica gel column. Eluting with mixtures of EtOAc:PE –
1:30 and gradual change until 1:9 and then flashed with
EtOAc afforded the sufficiently pure product as a yellow
oil in 89% yield (480 mg, 1.78 mmol). 1H NMR (200 MHz,
CDCl3) δ 7.52 – 7.37 (m, 2H), 7.31 – 7.23 (m, 3H), 3.81 –
3.70 (t, J = 4.4 Hz, 4H), 2.79 – 2.65 (t, J = 4.9 Hz, 4H),
2.07 – 1.95 (d, J = 12.2 Hz, 2H), 1.73 – 1.40 (m, 8H,
overlapping peaks). 13C{1H} NMR (50 MHz, CDCl3) δ
132.0, 128.5, 128.0, 123.6, 89.9, 86.7, 67.6, 59.0, 46.8,
35.6, 25.9, 22.9.[61]
1
solvent peak as a reference. H-NMR spectroscopic data
are given in the following order: chemical shift,
multiplicity (s, singlet, d, doublet, t, triplet, q, quartet, m,
multiplet), the J coupling constant in Hertz (Hz), and the
number of protons. The GC-MS spectra were recorded
with a Shimandzu® GCMS-QP2010 Plus, Chromatograph
Mass Spectrometer using a MEGA® (MEGA-5, F.T: 0.25
o
μm, I.D.: 0.25 mm, L: 30 m, Tmax: 350 C, Column ID#
11475) column, using n-octane as the internal standard.
HRMS spectra were recorded in a QTOF maxis Impact
(Bruker®) spectrometer with Electron Spray Ionization
(ESI)
General procedure
Unless otherwise noted, the following procedure was used
for all reactions: In a Teflon seal screw-cap pressure tube
which had been flame-dried and was equipped with a
stirring bar and a rubber septum was added 5 mol% MnBr2
(21.5 mg, 0.1 mmol). Under an argon flow, 2.0 mmol of
the amine were added and the mixture was stirred.
Subsequently, 2.0 mmol of the corresponding alkyne were
added and the mixture was stirred at room temperature and
under an argon flow until the solid was either completely
or partially dissolved. Briefly after the dissolution of the
inorganic material, 2.0 mmol of the ketone were added and
the rubber septum was replaced by a Teflon seal screw-cap
under an argon flow. The reaction mixture was stirred in an
Modified procedure for the synthesis of 4-(1-
(phenylethynyl)cyclohexyl)morpholine (4x) on a gram
scale under air.
o
oil bath, preheated at 130 C, for 20 hours. After removal
A Teflon seal screw-cap pressure tube equipped with a
stirring bar was charged with 5 mol% MnBr2 (107.3 mg,
0.5 mmol). Under air, 10.0 mmol of morpholine (0.871 g,
0.875 mL) were added and the mixture was stirred. 10.0
mmol of phenylacetylene (1.02 g, 1.10 mL) were added
and the mixture was stirred at room temperature until the
solid was completely dissolved. Finally, 10.0 mmol of
cyclohexanone (0.981 g, 1.04 mL) were added and the
pressure tube was quickly sealed by a Teflon seal screw-
cap. The reaction reaction mixture was stirred in an oil
from the heating apparatus and cooling to room
temperature, ethyl acetate was added (10 mL) and the
mixture was stirred for 5 minutes in order to completely
remove and dissolve the viscous mixture from the vessel’s
inner walls (this procedure was done twice, with 5 mL of
solvent each time). The resulting mixture was filtered
through a short silica gel plug in order to filter off
inorganic materials, the filtrate was concentrated under
vacuum and then loaded onto a silica gel column (if the
compound was insoluble into the eluents’ system, dry
loading of the crude mixture was performed). Gradient
column chromatography (usually of 15.0 cm length and 3.5
cm width and eluents’ flow set at 2.0 cm/min) with ethyl
acetate/petroleum ether provided the desired products. All
o
bath, preheated at 130 C, for 20 hours. After allowing the
mixture to cool to room temperature, ethyl acetate was
added (2x10 mL) and the mixture was stirred rapidly for 5
minutes before being transferred to a round bottom flask.
The mixture was concentrated under vacuum, and loaded
atop a silica gel column. Eluting with mixtures EtOAc/PE
– 1 : 30 and gradual change until 1 : 9 and then flashed
with EtOAc afforded the sufficiently pure product as a
yellow oil in 93% yield (2.50 g, 9.30 mmol). 1H NMR (200
MHz, CDCl3) δ 7.52 – 7.37 (m, 2H), 7.31 – 7.23 (m, 3H),
3.81 – 3.70 (t, J = 4.4 Hz, 4H), 2.79 – 2.65 (t, J = 4.9 Hz,
4H), 2.07 – 1.95 (d, J = 12.2 Hz, 2H), 1.73 – 1.40 (m, 8H,
overlapping peaks).[122]
1
products were characterized by H NMR, 13C{1H} NMR,
and HRMS, which were all in agreement with the assigned
structures.
Modified procedure for the synthesis of 3-(1-(1-
(phenylethynyl)cyclopentyl)pyrrolidin-2-yl)pyridine
(4zd single diastereoisomer).
The general reaction setup was carried out. After cooling
the reaction to room temperature, crystals started to form.
Ethyl acetate was added (2x5 mL), the mixture was stirred
rapidly until all viscous materials were removed from the
reaction vessel and inorganic materials were filtered off by
passing the mixture through a short silica gel plug. The
yellow solution was allowed to cool overnight, and pale-
Characterization data for new compounds
1-(1-(p-tolylethynyl)cyclohexyl)pyrrolidine
(4n):
Prepared according to the general procedure and obtained
as pale yellow crystals in 87% yield (465 mg, 1.74 mmol).
1H NMR (200 MHz, CDCl3) δ 7.36 – 7.29 (d, J = 8.1 Hz,
yellow crystals precipitated. The solid was filtered on a frit, 2H), 7.14 – 7.06 (d, J = 8.1 Hz, 2H), 2.89 (d, J = 6.0 Hz,
washed with cold ethyl acetate and dried under vacuum.
The final product was obtained as yellow crystals in 88%
yield (557 mg, 1.76 mmol). 1H NMR (200 MHz, CDCl3) δ
8.65 – 8.59 (s, 1H) , 8.49 – 8.38 (d, J = 8.6 Hz, 1H), 7.82 –
7.69 (d, J = 12.8 Hz, 1H), 7.51 – 7.37 (m, 2H), 7.34 – 7.13
(m, 4H), 4.30 – 4.22 (dd, J = 7.4, 17.7 Hz, 1H), 3.28 – 3.16
(s, 1H), 3.12 – 2.92 (q, J = 16.8 Hz, 1H), 2.42 – 2.09 (p, J
= 16.4 Hz, 2H), 2.05 – 1.42 (m, 10H, overlapping peaks).
13C{1H} NMR (50 MHz, CDCl3) δ 149.2, 147.9, 143.9,
134.8, 132.0, 128.5, 128.0, 123.8, 123.3, 92.2, 84.1, 67.0,
62.5, 51.7, 40.9, 40.8, 36.7, 24.2, 23.3, 22.8. HRMS (ESI-
TOF) m/z [M+H]+ calcd for C22H25N2 317.2012; Found
317.2018.
4H), 2.34 (s, 3H), 2.03 (t, J = 5.2 Hz, 2H), 1.84 (p, J = 3.3
Hz, 4H), 1.73 – 1.66 (t, 8H, overlapping peaks). 13C{1H}
NMR (50 MHz, CDCl3) δ 138.2, 131.9, 129.2, 120.4, 88.7,
87.0, 60.5, 47.5, 37.7, 25.7, 23.8, 23.3, 21.7. HRMS (ESI-
TOF) m/z [M+H]+ calcd for C19H26N 268.2060; Found
268.2064.
2-methyl-4-(1-(2-(pyridin-3-yl)pyrrolidin-1-
yl)cyclohexyl)but-3-yn-2-ol (4r, single diastereoisomer):
Prepared according to the general procedure and obtained
as pale yellow crystals in 81% yield (506 mg, 1.66 mmol)
1
1
and >99:1 d.r. according to H NMR. H NMR (200 MHz,
CDCl3) δ 8.55 (s, 1H), 8.37 (d, J = 4.8 Hz, 1H), 7.71 (d, J
= 7.8 Hz, 1H), 7.16 (t, J = 6.4 Hz, 1H), 4.21 (d, J = 9.4 Hz,
1H), 3.41 (s, 1H), 3.12 (t, J = 6.0 Hz, 1H), 2.81 (q, J = 8.3
Hz, 1H), 2.15 – 1.93 (m, 1H), 1.93 – 1.74 (m, 2H), 1.80 –
Modified procedure for the synthesis of 4-(1-
(phenylethynyl)cyclohexyl)morpholine (4x) under air.
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000566
Advanced Synthesis & Catalysis
1.60 (m, 3H), 1.55 (s, 6H), 1.49 – 1.32 (m, 5H), 1.34 –
1.15 (m, 2H), 1.10 – 0.83 (m, 3H). 13C{1H} NMR (50
MHz, CDCl3) δ 148.2, 147.0, 145.3, 134.8, 123.2, 90.6,
82.7, 64.7, 60.3, 60.0, 49.8, 39.4, 38.2, 36.2, 32.5, 25.6,
23.8, 23.1, 23.0. HRMS (ESI-TOF) m/z [M+H]+ calcd for
C20H29N2O 313.2274 ; Found 313.2275.
NMR (50 MHz, CDCl3) δ 131.9, 128.4, 127.9, 123.9, 91.4,
85.1, 65.9, 49.5, 40.7, 23.9, 23.7.[70]
1-(1-(phenylethynyl)cyclohexyl)pyrrolidine
(4e):
Prepared according to the general procedure and obtained
as an orange/yellow oil in 91% yield (461 mg, 1.82 mmol).
1H NMR (200 MHz, CDCl3) δ 7.44 (dd, J = 6.7, 3.1 Hz,
2H), 7.30 (m, 3H), 2.82 (t, J = 5.9 Hz, 4H), 2.13 – 1.94 (m,
2H), 1.91 – 1.41 (m, 12H, overlapping peaks). 13C{1H}
NMR (50 MHz, CDCl3) δ 131.7, 128.1, 127.6, 123.6, 90.3,
86.1, 59.3, 47.0, 37.8, 25.7, 23.5, 23.0.[76]
1-(1-((4-chlorophenyl)ethynyl)cyclohexyl)pyrrolidine
(4s): Prepared according to the general procedure and
obtained as pale yellow crystals in 77% yield (440 mg,
1.53 mmol). 1H NMR (200 MHz, CDCl3) δ 7.40 – 7.25 (d,
J = 8.5 Hz, 2H), 7.22 – 7.14 (d, J = 8.5 Hz, 2H), 2.76 –
2.67 (t, J = 5.8 Hz, 4H), 2.00 – 1.88 (d, J = 8.0 Hz, 2H),
1.81 – 1.38 (m, 12H, overlapping peaks). 13C{1H} NMR
(50 MHz, CDCl3) δ 133.8, 133.1, 128.6, 122.4, 91.9, 85.2,
59.5, 47.2, 38.0, 25.9, 23.7, 23.2. HRMS (ESI-TOF) m/z
[M+H]+ calcd for C18H23ClN 288.1514; Found 288.1510.
1-(3-methyl-1-phenylhex-1-yn-3-yl)pyrrolidine
(4g):
Prepared according to the general procedure and obtained
as an orange/brown oil in 48% yield (232 mg, 0.96 mmol).
1H NMR (200 MHz, CDCl3) δ 7.45 – 7.36 (m, 2H), 7.28 –
7.25 (m, 3H), 2.79 (t, J = 5.4 Hz, 4H), 1.85 – 1.74 (m, 4H),
1.73 – 1.47 (m, 4H), 1.43 (s, 3H), 0.95 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (50 MHz, CDCl3) δ 132.0, 128.4, 127.9,
123.8, 91.5, 84.7, 58.3, 48.0, 44.0, 26.1, 23.9, 18.0,
14.8.[76]
1-(1-((4-chlorophenyl)ethynyl)cyclohexyl)piperidine
(4t): Prepared according to the general procedure and
obtained as pale yellow crystals in 64% yield (380 mg,
1.26 mmol). 1H NMR (200 MHz, CDCl3) δ 7.39 – 7.29 (d,
J = 8.7 Hz, 2H), 7.26 – 7.19 (d, J = 8.7 Hz, 2H), 2.63 (t, J
= 5.0, 3.6 Hz, 4H), 2.03 (d, J = 9.9 Hz, 2H), 1.53 (m, 14H,
overlapping peaks). 13C{1H} NMR (50 MHz, CDCl3) δ
133.8, 133.1, 128.7, 122.5, 92.1, 85.2, 59.5, 47.4, 35.9,
26.8, 25.9, 24.9, 23.3. HRMS (ESI-TOF) m/z [M+H]+
calcd for C19H25ClN 302.1670; Found 302.1670.
1-(3-ethyl-1-phenylpent-1-yn-3-yl)pyrrolidine
(4h):
Prepared according to the general procedure and obtained
1
as a yellow oil in 32% yield (154 mg, 0.64 mmol). H
NMR (200 MHz, CDCl3) δ 7.41 (dd, J = 6.7, 3.1 Hz, 2H),
7.32 – 7.23 (m, 3H), 2.78 (s, 4H), 1.88 – 1.66 (m, 8H,
overlapping peaks), 0.96 (t, J = 7.4 Hz, 6H). 13C{1H} NMR
(50 MHz, CDCl3) δ 131.9, 128.3, 127.7, 123.8, 91.5, 85.0,
62.2, 47.6, 29.0, 23.7, 8.3.[81]
1-(phenylethynyl)-N,
N-dipropylcyclohexan-1-amine
(4zc): Prepared according to the general procedure and
obtained as a pale - yellow oil in 61% yield (346 mg, 1.22
mmol). 1H NMR (200 MHz, CDCl3) δ 7.54 – 7.37 (m, 2H),
7.34 – 7.20 (m, 3H), 2.75 – 2.51 (t, J = 7.8 Hz, 4H), 2.23 –
1.99 (d, J = 11.2 Hz, 2H), 1.78 – 1.37 (m, 12H,
overlapping peaks), 1.02 – 0.70 (t, J = 7.3 Hz, 6H).
13C{1H} NMR (50 MHz, CDCl3) δ 131.8, 128.4, 127.7,
124.3, 93.3, 85.1, 59.8, 52.7, 37.5, 29.9, 26.0, 23.5, 23.3,
12.2. HRMS (ESI-TOF) m/z [M+H]+ calcd for C20H30N
284.2373; Found 284.2374.
1-(4-(phenylethynyl)decan-4-yl)pyrrolidine
(4i):
Prepared according to the general procedure and obtained
1
as a yellow oil in 68% yield (424 mg, 1.36 mmol). H
NMR (200 MHz, CDCl3) δ 7.41 (dd, J = 6.6, 3.1 Hz, 2H),
7.32 – 7.24 (m, 3H), 2.76 (s, 4H), 1.88 – 1.58 (m, 8H,
overlapping peaks), 1.51 – 1.18 (m, 10H), 1.00 – 0.77 (m,
6H). 13C{1H} NMR (50 MHz, CDCl3) δ 131.7, 128.2,
127.6, 123.7, 91.6, 84.7, 61.3, 47.5, 39.4, 37.1, 31.9, 29.8,
23.6, 22.8, 17.2, 14.6, 14.2.[81]
Characterization data for known compounds
1-(2-(4-methoxyphenyl)-4-phenylbut-3-yn-2-
yl)pyrrolidine (4j): Prepared according to the general
procedure and obtained as a yellow oil in 34% yield (208
1-(1-(phenylethynyl)cyclohexyl)piperidine
(4a):
1
Prepared according to the general procedure and obtained
mg, 0.68 mmol). H NMR (200 MHz, CDCl3) δ 7.76 –
1
as a yellow oil in 97% yield (519 mg, 1.94 mmol). H
7.63 (d, J = 8.7 Hz, 2H), 7.59 – 7.46 (dd, J = 2.7, 6.1 Hz,
2H), 7.41 – 7.29 (m, 3H), 6.95 – 6.83 (d, J = 8.7 Hz, 2H),
3.91 – 3.76 (s, 3H), 2.83 – 2.69 (m, 2H), 2.69 – 2.54 (m,
2H), 1.91 – 1.75 (m, 4H), 1.78 – 1.69 (s, 3H). 13C{1H}
NMR (50 MHz, CDCl3) δ 158.9, 138.2, 132.1, 128.6,
128.2, 127.8, 123.7, 113.6, 89.9, 87.4, 62.3, 55.5, 48.7,
32.6, 24.1.[68]
NMR (200 MHz, CDCl3) δ 7.47 – 7.36 (m, 2H), 7.28 –
7.23 (m, 3H), 2.66 (s, 4H), 2.11– 2.05 (m, 2H), 1.83 – 1.34
(m, 14H, overlapping peaks). 13C{1H} NMR (50 MHz,
CDCl3) δ 131.9, 128.4, 127.8, 124.0, 91.1, 86.3, 59.5, 47.4,
36.0, 26.9, 26.0, 25.0, 23.3.[63,70,76]
1-(1-(phenylethynyl)cyclopentyl)piperidine
(4b):
Prepared according to the general procedure and obtained
1-(2-(4-chlorophenyl)-4-phenylbut-3-yn-2-
1
as a yellow oil in 67% yield (339 mg, 1.34 mmol). H
yl)pyrrolidine (4k): Prepared according to the general
procedure and obtained as a yellow oil in in 42% yield
NMR (200 MHz, CDCl3) δ 7.41 (dd, J = 6.5, 3.2 Hz, 2H),
7.31 – 7.25 (m, 3H), 2.65 – 2.62 (m, 4H), 2.13 – 2.10 (m,
2H), 1.87 – 1.44 (m, 12H, overlapping peaks). 13C{1H}
NMR (50 MHz, CDCl3) δ 131.9, 128.4, 127.8, 124.0, 91.6,
85.4, 67.7, 50.5, 40.1, 26.4, 24.7, 23.6.[70]
1
(260 mg, 0.84 mmol). H NMR (200 MHz, CDCl3) δ 7.87
– 7.71 (d, J = 8.3 Hz, 2H), 7.66 – 7.53 (m, 2H), 7.47 – 7.30
(m, 5H, overlapping peaks), 2.87 – 2.75 (m, 2H), 2.72 –
2.59 (m, 2H), 1.91 – 1.79 (m, 4H), 1.82 – 1.70 (s, 3H).
13C{1H} NMR (50 MHz, CDCl3) δ 144.7, 133.0, 132.2,
128.6, 128.5, 128.4, 128.2, 123.5, 89.1, 87.8, 62.5, 48.7,
32.8, 24.2.[68]
1-(1-(phenylethynyl)cycloheptyl)pyrrolidine
(4c):
Prepared according to the general procedure and obtained
1
as a yellow oil in 73% yield (390 mg, 1.46 mmol). H
NMR (200 MHz, CDCl3) δ 7.42 (dd, J = 6.6, 3.1 Hz, 2H),
7.28 (dd, J = 6.6, 2.7 Hz, 3H), 2.79 (t, J = 6.0 Hz, 4H),
1-(1-(m-tolylethynyl)cyclohexyl)piperidine
Prepared according to the general procedure and obtained
(4m):
1
2.10 – 1.83 (m, 4H, overlapping peaks), 1.78 (p, J = 3.2 Hz, as a yellow oil in 81% yield (456 mg, 1.64 mmol). H
4H), 1.71 – 1.46 (m, 8H, overlapping peaks). 13C{1H}
NMR (50 MHz, CDCl3) δ 132.0, 128.4, 128.0, 123.7, 91.4,
85.3, 63.3, 48.2, 40.0, 28.2, 24.0, 22.4.[70]
NMR (200 MHz, CDCl3) δ 7.25 – 7.03 (m, 4H), 2.77 –
2.61 (t, J = 3.0, 3.9 Hz, 4H), 2.36 – 2.30 (s, 3H), 2.15 –
2.03 (d, J = 12.1 Hz, 2H), 1.85 – 1.34 (m, 14H,
overlapping peaks). 13C{1H} NMR (50 MHz, CDCl3) δ
137.9, 132.3, 128.8, 128.6, 128.1, 123.6, 90.3, 86.4, 59.5,
47.2, 35.8, 26.6, 25.8, 24.8, 23.2, 21.3.[81]
1-(1-(phenylethynyl)cyclopentyl)pyrrolidine
(4d):
Prepared according to the general procedure and obtained
as an orange/yellow oil in 75% yield (359 mg, 1.50 mmol).
1H NMR (200 MHz, CDCl3) δ 7.48 – 7.35 (m, 2H), 7.33 –
7.17 (m, 3H), 2.88 – 2.61 (t, J = 6.7 Hz, 4H), 2.21 – 1.98
(m, 2H), 1.93 – 1.64 (m, 10H, overlapping peaks). 13C{1H}
1-(1-(p-tolylethynyl)cyclohexyl)piperidine (4o): Prepared
according to the general procedure and obtained as a
1
yellow oil in 70% yield (394 mg, 1.40 mmol). H NMR
10
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000566
Advanced Synthesis & Catalysis
(200 MHz, CDCl3) δ 7.33 (d, J = 6.5 Hz, 2H), 7.09 (d, J =
CDCl3) δ 131.6, 128.1, 127.7, 123.6, 93.3, 84.6, 55.2, 43.2,
6.5 Hz, 2H), 2.69 (s, 4H), 2.33 (s, 3H), 2.14 – 2.07 (m, 2H), 38.1, 31.8, 30.5, 29.5, 29.3, 27.5, 25.9, 23.1, 22.7, 14.1.[81]
1.73 – 1.44 (m, 14H, overlapping peaks). 13C{1H} NMR
(50 MHz, CDCl3) δ 137.9, 131.8, 129.2, 120.8, 90.1, 86.4,
N-cyclohexyl-1-(phenylethynyl)cyclohexan-1-amine
59.9, 47.3, 35.9, 26.6, 25.9, 24.9, 23.4, 21.6.[70]
(4zb): Prepared according to the general procedure and
obtained as a yellowish oil in 58% yield (326 mg, 1.16
1-(1-((4-methoxy-2-
mmol). 1H NMR (200 MHz, CDCl3) δ 7.46 – 7.35 (m, 2H),
7.33 – 7.23 (m, 3H), 2.98 – 2.71 (dt, J = 6.6, 10.2 Hz, 1H),
2.04 – 1.84 (d, J = 10.2 Hz, 4H), 1.79 – 1.49 (m, 6H), 1.50
– 1.01 (m, 10H, overlapping peaks). 13C{1H} NMR (50
MHz, CDCl3) δ 131.7, 128.5, 127.9, 124.1, 94.6, 84.1, 55.4,
52.8, 39.5, 36.8, 26.0, 26.0, 26.0, 23.4.[128]
methylphenyl)ethynyl)cyclohexyl)piperidine
(4p):
Prepared according to the general procedure and obtained
as a yellow crystals in 89% yield (554 mg, 1.78 mmol). H
1
NMR (200 MHz, CDCl3) δ 7.34 (d, J = 8.4 Hz, 1H), 6.73
(s, 1H), 6.66 (d, J = 8.5 Hz, 1H), 3.77 (s, 3H), 2.73 – 2.63
(m, 4H), 2.42 (s, 3H), 2.11 (d, J = 11.5 Hz, 2H), 1.75 –
1.52 (m, 10H, overlapping peaks), 1.55 – 1.37 (m, 4H,
overlapping peaks). 13C{1H} NMR (50 MHz, CDCl3) δ
159.1, 141.5, 133.3, 116.0, 115.0, 111.1, 92.9, 84.8, 59.7,
55.3, 47.2, 36.0, 26.6, 25.8, 24.8, 23.3, 21.5.[81]
Acknowledgements
This work was supported by the Hellenic Foundation for
Research and Innovation (H.F.R.I.) under the “First Call for
H.F.R.I. Research Projects to support Faculty members and
Researchers and the procurement of high-cost research
equipment grant” (Project Number: 16 – Acronym: SUSTAIN),
as well as by European Funding: Horizon 2020-MSCA (ITN-EJD
CATMEC 14/06-721223). The contribution of COST Action
CA15106 (C-H Activation in Organic Synthesis - CHAOS) is also
gratefully acknowledged. Moreover, we are thankful for the
human and technical support provided by the IZO-SGI SGIker of
UPV/EHU. Mr. Savvas G. Chalkidis is gratefully acknowledged
for the synthesis and characterization of compound 4w.
1-(1-((4-methoxyphenyl)ethynyl)cyclohexyl)piperidine
(4q): Prepared according to the general procedure and
obtained as yellow crystals in 87% yield (517 mg, 1.74
1
mmol). H NMR (200 MHz, CDCl3) δ 7.48 – 7.22 (d, J =
8.9 Hz, 2H), 6.92 – 6.70 (d, J = 8.9 Hz, 2H), 3.98 – 3.47 (s,
3H), 2.68 – 2.62 (t, J = 5.3 Hz, 4H), 2.31 – 1.91 (d, J =
12.7 Hz, 2H), 1.80 – 1.37 (m, 14H, overlapping peaks).
13C{1H} NMR (50 MHz, CDCl3) δ 159.3, 133.2, 116.2,
114.0, 89.3, 86.0, 59.4, 55.4, 47.3, 36.1, 26.9, 26.0, 25.0,
23.3.[127]
1-(1-((2-bromophenyl)ethynyl)cyclohexyl)piperidine
(4u): Prepared according to the general procedure and
obtained as an orange oil in 57% yield (395 mg, 1.14
mmol). 1H NMR (200 MHz, CDCl3) δ 7.67 – 7.37 (m, 2H,
overlapping peaks), 7.29 – 7.06 (m, 2H, overlapping
peaks), 2.83 – 2.64 (t, J = 5.5 Hz, 4H), 2.25 – 2.09 (d, J =
11.6 Hz, 2H), 1.89 – 1.35 (m, 14H, overlapping peaks).
13C{1H}NMR (50 MHz, CDCl3) δ 133.7, 132.5, 129.0,
127.1, 126.0, 125.7, 96.1, 85.0, 59.9, 47.4, 35.9, 26.8, 25.9,
25.0, 23.4.[81]
This work is dedicated to Professor Robert H. Grubbs, on the
occasion of the 50-year anniversary of his independent research.
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This article is protected by copyright. All rights reserved.

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Manganese-Catalyzed Multicomponent Synthesis
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Adv. Synth. Catal. Year, Volume, Page – Page
Stavros P. Neofotistos, Nikolaos V. Tzouras,
Martin Pauze, Enrique Gómez-Bengoa, and
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