Copper-catalyzed hydroamination of alkynes with aliphatic amines: Regioselective access to (1 E,3 E)-1,4-disubstituted-1,3-dienes

Article abstract of DOI:10.1021/acs.orglett.5b00177

Copper-catalyzed hydroamination of aromatic or heteroaromatic alkynes with cyclic secondary aliphatic amines undergoes generation of an enamine-type intermediate. The latter is transformed in situ via a coupling reaction with a second molecule of alkyne to afford regioselectively (1E,3E)-1,4-disubstituted-1,3-dienes with the formation of C-N, C-C, and C-H bonds.

Full text of DOI:10.1021/acs.orglett.5b00177

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Hydroamination of Alkynes with Aliphatic Amines:
Regioselective Access to (1E,3E)‑1,4-Disubstituted-1,3-dienes
Janet Bahri,†,‡ Bassem Jamoussi,‡ Arie van Der Lee,§ Marc Taillefer,*,† and Florian Monnier*,†
†Ecole Nationale Super
Normale, 34296 Montpellier Cedex 05, France
́
ieure de Chimie de Montpellier, Institut Charles Gerhardt, CNRS UMR 5253, AM2N, 8 rue de l’Ecole
‡Laboratoire de Chimie, Institut Super
́
ieur d’Education et de Formation Continue, 43 Rue de la Liberte,
́
2019, Le Bardo, Tunisie
§IEM Universite
́
Montpellier, 2 Case courrier 047 Place Eugene Bataillon, 34095 Montpellier cedex 5, France
̀
S
* Supporting Information
ABSTRACT: Copper-catalyzed hydroamination of aromatic
or heteroaromatic alkynes with cyclic secondary aliphatic
amines undergoes generation of an enamine-type intermediate.
The latter is transformed in situ via a coupling reaction with a
second molecule of alkyne to afford regioselectively (1E,3E)-
1,4-disubstituted-1,3-dienes with the formation of C−N, C−C,
and C−H bonds.
he development of clean syntheses with respect to atom
As part of our studies on copper-catalyzed cross-coupling
Teconomy by the selective combination of several reactions,10 herein we report a one-pot regioselective access to
(1E,3E)-1,4-disubstitued-1,3-dienes via a sequential formation
of C−N, C−H and C−C bonds relative to a hydroamination-
type intermediate. The synthesis of this original class of
complex molecules is catalyzed by a simple copper salt (CuCl)
without any additive ligands, and is made from the reaction of 2
equiv of terminal arylacetylenes with cyclic secondary aliphatic
amines. It is noteworthy that dienamine chemistry is a valuable
tool in organic chemistry, especially in bioactive molecules,
natural products, and organocatalysis.11
Initial tests were done on phenylacetylene (2 mmol) and
morpholine (5 mmol) as model substrates with a ligandless
copper catalyst (2.5 mol % of Cu(0), Cu(I), or Cu(II)
catalysts) in NMP to observe the reactivity of this system
(Table 1). First, we observed a mixture of classical hydro-
amination products such as enamine coming from the
Markovnikov and anti-Markovnikov addition of morpholine,
respectively 2a and 3a (only observed by GC-MS due to a rapid
degradation), and a degradation product 4a coming from
hydrolysis of 3a (Table 1, entries 1−8). In all cases, molecules
2a, 3a, and 4a were unselectively observed in low to fair yields.
Surprisingly, whatever the copper source, we also observed an
unexpected product 1a in moderate to large amounts. After
purification and isolation of the latter, we identified 1a as 4-
((1E,3E)-1,4-diphenylbuta-1,3-dien-1-yl)morpholine. We rap-
idly thought that the formation of this compound was
synthetically interesting as, to the best of our knowledge,
there is no precedent in the literature of this kind of high-
valued molecule synthesis.11
molecules into only one product is receiving increasing
interest.1 Molecular catalysts are currently playing a key role
in such innovative synthetic methods.2 Transition metal
catalysts allow the synthesis of complex targeted molecules
through highly simplified routes involving the combination of
simple and readily available substrates and the formation of
several consecutive bonds with high selectivity. Alkyne and
amine molecules emerged as attractive substrates because the
addition of N-nucleophiles (N−H) to triple C−C bonds
affords a high-valued molecule via a hydroamination-type
reaction with the formation of C−N and C−H bonds.3 This
type of reaction is a major goal for chemists to obtain
functionalized unsaturated amines via a 100% atom-economical
pathway.4 Recently, hydroamination mediated by acids, bases,
alkaline earth metals, lanthanides, and actinides has been
performed.5 Transition-metal-catalyzed hydroamination of
alkynes has also been developed in recent years,6 notably
with Ag, Au, Pt, Pd, Rh, Ir, and Ru catalysts. Unlike these
expensive metal sources, cheaper and more sustainable metals
such as copper have received limited attention.7 Thus, most of
the Cu-catalyzed hydroamination reactions have been described
in an intramolecular fashion to afford N-heterocycles.8 Only a
few reports have been developed for intermolecular reactions.
Most of them make use of heterogeneous copper-supported
catalysts and are limited to the formation of imines from
primary amines.9 Only one example of a simple hydroamination
of terminal alkynes with anilines affording the corresponding
imines has been described (with CuCl used in homogeneous
conditions).7d The principal limitation of these copper catalysts
is the exclusive use of primary amines as substrates. Thus, there
is a need to discover a novel and simple system to extend the
copper-catalyzed hydroamination of alkynes to secondary
amines to produce enamines and dieneamines.
Following this initial success, we decided to focus on the
optimization of the reaction conditions to afford 1a in the most
Received: January 19, 2015
Published: February 23, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00177
Org. Lett. 2015, 17, 1224−1227

Organic Letters
Letter
Table 1. Hydroamination of Phenylacetylene: Parametric
Study
Scheme 1. Reaction Scope with Various Six-Membered Ring
Amines (Isolated Yields)
ab
,
corresponding target dienes 1a, 1b, 1c, and 1d respectively in
72%, 70%, 67%, and 70% isolated yields.
Furthermore, we could isolate crystals of 1c that were
suitable for X-ray structure analysis (CCDC 1029186) (Figure
1). The structure revealed the relative spatial position of the
entry
solvent
[Cu]
CuBr
t, °C
1a
2a
3a
4a
1
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMA
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
25
53
55
30
12
40
10
25
75
60
10
12
0
20
18
5
10
12
5
17
15
10
12
10
9
2
CuI
3
Cu2O
CuCN
CuF2
CuO
4
10
13
5
7
5
10
5
6
7
CuBr2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
Cu(acac)2
CuCl
CuCl
CuCl
−
5
4
11
15
20
16
18
35
10
10
11
10
0
8
4
6
9
10
70
65
60
65
20
45
7
10
4
10
11
12
13
14
15
16
17
18
19
DMSO
dioxane
HMPA
CH3CN
toluene
NMP
NMP
NMP
NMP
NMP
5
5
0
5
0
7
Figure 1. ORTEP drawing of the molecular structure of 1c (nitrogen
atom in blue).
0
5
37
0
5
5
0
piperidine substituent on the first double bond. The structure
also reveals the stereochemistry of both double bonds (e.g.,
1E,3E) and the trans junction between them. All these
observations were correlated by NMR experiments and the
different coupling constants observed in all the 1H NMR
spectra of 1,4-disubstituted-1,3-dienes 1a−1t.
90
12
14
0
5
3
5
μW
120
35
0
45
0
6
20
0
a
Conditions: phenylacetylene (2 mmol), morpholine (5 mmol), CuCl
b
(0,05 mmol), 2 mL of solvent, 12 h of reaction. GC Yields with 1,3,5-
trimethoxybenzene as internal standard.
We also demonstrated that this original method is tolerant of
cyclic amines of various sizes and different substitutions. Thus,
under classical conditions, it was shown that the reaction
proceeds with very good selectivities starting from pyrrolidine,
piperidine, and azepane, the corresponding products 1e, 1c,
and 1f being obtained respectively in 63%, 67%, and 60% yields
(Scheme 2).
selective manner. As resumed in Table 1, we found that CuCl
was the most efficient copper source (Table 1, entries 1−8)
associated with the NMP as solvent (Table 1, entries 8−15) for
the generation of 1a in 75% NMR yield (entry 8). We also
showed that thermal activation at 120 °C is needed for the
synthesis of 1a as neither rt nor 90 °C allow good formation of
the desired product. Activation by microwaves is also unsuitable
for this transformation (Table 1, entry 19). It is noteworthy
that none of the products 1a−4a were observed in the absence
of any copper sources (entry 20). We also observed an
important decrease in yields and selectivities if we add <2.5
equiv of morpholine or <2.5 mol % of CuCl. At this stage of the
investigation, we were able to selectively isolate 75% of 1a
starting from 1 mmol of phenylacetylene (with a second
addition after 2 h of reaction at 120 °C) and 2.5 mmol of
morpholine catalyzed by 2.5 mol % of CuCl in NMP at 120 °C
over 12 h.12
Scheme 2. Scope of the Reaction with Differents Sizes of
Cyclic Amines (Isolated Yields)
On the basis of these results, we wished to demonstrate
further the efficiency and functional group tolerance of this
novel reaction by varying substitution on aryl acetylenes and
amines. First, we were able to apply our method to various
cyclic secondary amines (Scheme 1).13 Phenylacetylene easily
reacted under optimized conditions with morpholine, thio-
morpholine, piperidine, and 4-methylpiperazine to afford the
We also noted that substitutions on the piperidine partner
did not affect the reactivity, as we isolated the corresponding
dienes 1g and 1h in 64% and 62% yields (Scheme 3).
Then, we decided to investigate the scope of this
hydroamination process by evaluating a series of various
electronically varied arylacetylenes under one set of optimized
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Organic Letters
Letter
hydroamination reaction of an enamine-type intermediate
coordinated to copper, the latter being able to activate
(coordination/insertion) a second molecule of alkyne before
the formation and release of the dieneamine. Further
investigations on the mechanism of this reaction are in
progress.
Scheme 3. Examples from Substituted Piperidines (Isolated
Yields)
In summary, a novel type of functionalization of alkynes with
cyclic secondary amines has been developed. Starting from
these very accessible and simple substrates, a low catalytic
amount of CuCl allows regioselective one-pot access to
(1E,3E)-1,4-disubstitued-1,3-dienes. This reaction proceeds
via a sequential formation of C−N and C−C bonds relative
to a hydroamination-type intermediate. This original reaction
allows simple and cheap access to dienamines which are
valuable tools in bioactive-natural synthesis and in organo-
catalysis.
conditions (Scheme 4). Moderate to good yields were obtained
with terminal alkynes substituted on the aryl ring by methyl,
Scheme 4. Reaction Scope with Various Substituted
Arylacetylenes (Isolated Yields)
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and characterization data for
all new compounds, and X-ray structural data for 1c (CCDC
1029186). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: marc.taillefer@enscm.fr.
*E-mail: florian.monnier@enscm.fr.
Notes
tert-butyl, and thiomethyl groups (Scheme 4, products 1i−1k
and 1t). Additionally, we also tested para-halogenated aromatic
alkynes, and corresponding dienes were isolated in good yields
(for R = Br: 65% of 1l, for R = Cl: 66% of 1m, and for R = F:
63% of 1n).
Finally, we showed that this methodology is tolerant and
efficient if hetero- and polyaromatic alkynes are used as starting
materials (Figure 2). Under optimized conditions, we were able
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Authors thank CNRS, Proclean and Reg
Roussillon for support and Martin Pichette-Drapeau (Uni-
́
ion Languedoc-
versite
́
Laval, Canada) for proofreading this manuscript.
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