Diastereoselective synthesis of propargylamines catalyzed by Cu-MCM-41

Article abstract of DOI:10.1016/j.tetlet.2018.05.010

In this work, a rapid, efficient and protecting group free diastereoselective synthesis of propargylamines through a multicomponent coupling reaction between (S)-prolinol, phenylacetylene and commercially available aldehydes catalyzed by Cu-MCM-41 in hete

Full text of DOI:10.1016/j.tetlet.2018.05.010

Accepted Manuscript
Diastereoselective Synthesis of Propargylamines Catalyzed by Cu-MCM-41
Omar Cortezano-Arellano, Miguel A. Hernández-Gasca, Deyanira Ángeles-
Beltrán, Guillermo E. Negrón-Silva, Rosa Santillan
PII:
S0040-4039(18)30593-8
https://doi.org/10.1016/j.tetlet.2018.05.010
TETL 49957
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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19 January 2018
3 May 2018
4 May 2018
Please cite this article as: Cortezano-Arellano, O., Hernández-Gasca, M.A., Ángeles-Beltrán, D., Negrón-Silva,
G.E., Santillan, R., Diastereoselective Synthesis of Propargylamines Catalyzed by Cu-MCM-41, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.05.010
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Tetrahedron Letters
Diastereoselective Synthesis of Propargylamines Catalyzed by Cu-MCM-41
Omar Cortezano-Arellano,a Miguel A. Hernández-Gasca,a Deyanira Ángeles-Beltrán,a Guillermo E.
Negrón-Silvaa and Rosa Santillanb
aUniversidad Autónoma Metropolitana, Departamento de Ciencias Básicas. Av. San Pablo No. 180, Azcapotzalco, Ciudad de México. C.P.02200. México.
bDepartamento de Química CINVESTAV-IPN Apdo. Postal 14-740, 07000 Ciudad de México, México.
ARTICLE INFO
ABSTRACT
Article history:
Received
In this work, a rapid, efficient and protecting group free diastereoselective synthesis of
propargylamines through
a multicomponent coupling reaction between (S)-prolinol,
Received in revised form
Accepted
Available online
phenylacetylene and commercially available aldehydes catalyzed by Cu-MCM-41 in
heterogeneous phase is reported. The reactions were carried out under solvent free conditions
with good yields and moderate reaction times. In all the cases, catalyst was recovered and
reused up to five cycles. Recyclability of the catalyst, low catalyst loading, solvent and
protecting group free conditions, and the use of inexpensive catalyst are the key features that
provide green aspects to this synthetic protocol.
Keywords:
Propargylamines
Diastereoselectivity
Multicomponent reactions
Heterogeneous catalysis
Cu-MCM-41
2009 Elsevier Ltd. All rights reserved.
 Corresponding author.
e-mail: gns@correo.azc.uam.mx (G. E. Negrón-Silva).

Scheme 2 Cu-MCM-41 catalyzed A3 coupling.
Introduction
Propargylamines are present in several biomolecules1 and are
also important synthetic intermediates for the preparation of
many nitrogen-containing compounds.2 The traditional strategy
for the synthesis of propargylamines is the addition of a metal
acetylide to an imine group. However, the use of stoichiometric
amounts of strong bases for the generation of the organometallic
reagent as well as the moisture sensitivity of these reagents,
makes sometimes this strategy unattractive. The A3-coupling
approach is a convenient and atom economic method since the
direct nucleophilic addition occurs previous C-H activation of the
terminal alkynes to the C=N double bond of imine or iminium
ion in situ from aldehyde and an amine. (Scheme 1).3
To optimize, screening of a variety of reaction conditions
were studied (Table 1). To our delight, the reaction proceeded
successfully in the presence of 45 mg/mmol (2.87% wt of
copper) of Cu-MCM-41 solvent-free condition at 110 °C to
afford propargylamine 4 in good yield (Table 1, entry 10).
Entry
Catalyst
Temperature
Time
(h)
Yield
(mg/1 mmol of 1)
(°C)
rt
(%) of 4
1
10
20
45
20
45
20
45
45
45
45
1-48
1-48
1-48
1-48
1-48
1-48
1-48
1-48
1-48
20
0
0
2
rt
3
rt
0
4
50
50
70
85
90
100
110
0
5
0
6
traces
10
20
60
90
7
8
9
10
Table 1 Screening of Cu-MCM-41 catalyst for the synthesis of 4.
With the optimized reaction conditions, the scope and
limitations of the reaction were studied (Scheme 3). A variety of
commercial aldehydes (Table 2, entries 1-12) was investigated
and pyrrolidine 1 was replaced by (S)-prolinol 1a as a substrate
under the heterogenous catalysis. Pleasingly we found this
protocol to be very general for different aldehydes in a highly
stereoselectively fashion.
Scheme 1 Typical strategies for the synthesis of propargylamines.
Due to the extensive chemistry associated with these synthons,
significant efforts have been devoted to the development of
methodologies for their stereoselective preparation.4 The need for
the development of environmentally benign, efficient,
economical and green processes in which for example, the
catalyst could be recovered and recycled is mandatory.5 Thus,
heterogeneous catalysis has been employed to recover and reuse
the catalyst during several reaction cycles. Porous mesostructured
silicates type MCM-41 have attracted a great attention in
heterogeneous catalysis research since their first synthesis in
1992,6 because of their ordered porous and easily modifiable
large specific surface. However, in order to enhance their weak
catalytic ability, they have been modified by doping them with
transition metals such as Cu.7
Scheme 3 Cu-MCM-41 catalyzed A3 coupling with (S)-prolinol and
different aldehydes.
Cu-MCM-418 has been successfully used as a catalyst in
reactions such as: Baeyer-Villiger oxidation of cyclohexanones,9
synthesis of 5-substituted 1H-tetrazoles,10 likewise for efficient
synthesis of propargylamines in three-component coupling of
aldehydes, amines and alkynes.11
Based on the importance of the propargylamine moiety herein
we report a simple and efficient protocol for the addition of
reactive acetylides to iminium ions to afford diastereoselective
propargylamines using Cu-MCM-41 as catalyst and under
solvent-free conditions. The relationship between the catalytic
activity and the recyclability of the catalyst was also studied.
Results and Discussion
The Cu-MCM-41 was synthesized according to typical
procedure12 and the percentage of Cu content was estimated
(2.87% wt). To evaluate the catalytic activity of Cu-MCM-41,
benzaldehyde 3, pyrrolidine 1, and phenylacetylene 2 was tested
as a model reaction (Scheme 2).

Figure 1 Reuse of Cu-MCM-41 in the synthesis of 4a.
The recovered catalyst was characterized and shown to retain
its morphology intact even though the amount of copper
decreased notably from 2.87% wt to 0.71% wt (see Supporting
Information). Finally, with the aim of stablish the
stereochemistry of the new stereogenic center, we perform
different tests for the protection of OH group of 4a. Fortunately
we were pleased when we used the reaction conditions reported
by Deslogchamps13 using TBDPSCl and imidazole (Scheme 4).
Table 2 Screening of Cu-MCM-41 catalyst with several aldehydes
for the synthesis of propargylamines 4a-l.
[a] Isolated yields after flash chromatography. [b] Diastereomeric ratios
determined by 1H NMR spectroscopic analysis of the crude reaction mixture.
[c] glyoxal dimethyl acetal solution 60% wt in H2O.
Scheme 4
As seen in table 2, various aromatic and aliphatic aldehydes
were employed. Substituted benzaldehydes bearing at o-, m-, p-
positions hydroxy, methyl, methoxy and phenoxy groups,
generated the desired products 4a-4g in satisfactory yields and
diastereoselectivities (Table 2, entries 1-7).
The structure and absolute configuration of 5 was confirmed
by a single-crystal X-ray diffraction analysis14 (Figure 2) which
indicates that the newly formed stereocenter possesses the (S)
absolute configuration. The stereocenter of the other products
(4b-4l) was tentatively assigned as (S) by analogy.
The only heterocyclic aldehyde that was evaluated exhibited
high reactivity and diastereoselectivity to afford expected product
4h (entry 8). On the other hand, aliphatic aldehydes such as
hydroxycinnamaldehyde, 2-ethylbutyraldehyde and heptanal
(entries 9–11) also reacted under the optimized reaction
conditions, generating propargylamines 4i–4k in satisfactory
yields and diastereoselectivities.
Notably glyoxal dimethyl acetal (60% wt in H2O) tolerated the
reaction conditions (entry 12) furnishing the desired product 4l in
65% yield, albeit in a modest diastereoselectivity (entry 12). The
latter example showcases that, in contrast to classical acetylide
generation under strong basic conditions, water does not
considerably affect the chemical efficiency of the reaction in our
protocol, allowing the preparation of complex propargylamines
under mild and under non-inert conditions.
Figure 2 ORTEP drawing of compound 5.
A plausible mechanism for heterogeneous copper catalyzed
three-component coupling reaction is illustrated in Scheme 5.2d, 2l
First, (S)-prolinol 1 reacts with aldehyde 2, providing the
iminium intermediate A, an π-metal–alkyne complex B might be
formed first making the alkyne proton more acidic for further
abstraction in C. Subsequent attack of an in situ formed copper
acetylide D resulting in the formation of propargylamines 4a-l
with concomitant regeneration of the metal catalyst. Presumably,
the origin of diastereoselectivity may due to coordination of the
amino and hydroxyl moieties4j, 15 in the transition states C and D.
Next, the recyclability of the catalyst was studied (see
Supporting Information for details). The recovered catalyst
worked well up to four catalytic runs with marginal loss and a
decrease in chemical yield of 50% for the synthesis of 4a after 5
cycles (Figure 1). It should be mentioned that in all cases the
diastereoselectivity was conserved.

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Scheme 5 Plausible mechanism for diastereoselective synthesis of
propargylamines catalyzed by Cu-MCM-41.
Conclusions
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We demonstrated that Cu-MCM-41 is an efficient catalyst for
the diastereoselective synthesis of propargylamines through a
three component coupling between different commercial
aldehydes, (S)-prolinol, and phenylacetylene via C–H activation.
This method offers several advantages including solvent free
conditions, good yields, simple work-up, ease for separation, and
recycling of the catalyst, as well as a wide tolerance to different
functional groups in the aldehyde. Additionally, the catalyst
could be readily recovered and reusable up to five times thus
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experimental studies are in progress and will be reported soon.
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Diastereoselective Synthesis of
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Propargylamines Catalyzed by Cu-MCM-41
Omar Cortezano-Arellano, Miguel A. Hernández-Gasca, Deyanira Ángeles-Beltrán, Guillermo E. Negrón-
Silva* and Rosa Santillan
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Highligths
 Diastereoselective
propargylamines.
synthesis
of
 Multicomponent coupling reaction by a
simple catalyst in heterogeneous phase.
 The reactions were carried out under solvent
free conditions.
 The catalyst was recovered and reused up to
five cycles.