Hydroamination of terminal alkynes with secondary amines catalyzed by copper: Regioselective access to amines

Article abstract of DOI:10.1039/c5cc02677f

A simple and convenient copper-catalyzed hydroamination of arylacetylenes with secondary amines has been performed giving a simple access to aliphatic amines after reduction of the hydroaminated products (E-enamines). Here we described a mild catalytic system utilizing CuCN precatalyst without any additive ligands in a solvent-free system.

Full text of DOI:10.1039/c5cc02677f

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Hydroamination of terminal alkynes with
secondary amines catalyzed by copper:
Cite this:DOI: 10.1039/c5cc02677f
regioselective access to amines†
Received 31st March 2015,
Accepted 6th June 2015
Janet Bahri,ab Remi Blieck,a Bassem Jamoussi,b Marc Taillefer*a and
´
Florian Monnier*a
DOI: 10.1039/c5cc02677f
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A simple and convenient copper-catalyzed hydroamination of Several heterogeneous copper catalytic systems (Cu ion-exchange
arylacetylenes with secondary amines has been performed giving tungstophosphoric acid, montmorillonite) were reported for the
a simple access to aliphatic amines after reduction of the hydro- Markovnikov hydroamination of arylacetylenes with anilines.11
aminated products (E-enamines). Here we described a mild catalytic Verma et al. described the anti-Markovnikov addition of
system utilizing CuCN precatalyst without any additive ligands in a N-heterocycles with internal alkynes catalysed by Cu(I)/benzo-
solvent-free system.
triazole system.12 A simple CuCl catalyst has been used for the
Markovnikov hydroamination of terminal alkynes with anilines
The direct synthesis of aminated products is a highly desirable derivatives.13 Recently hydroamination of alkynes with electrophi-
transformation as amines are widely represented in bioactive lic amines catalysed by copper/ligand systems were described.14
compounds for human, animal and vegetal healthcare.1 Among Compared with extensive studies on this transformation with Rh,
the well-known syntheses of amines, hydroamination of alkynes Au, Ir and Pd-based catalysts, the copper-catalyzed methodologies
represent a total atom-economical transformation to achieve the are limited in terms of substrate scope (anilines derivatives and
direct synthesis of aminated products. Since the pioneering work aromatic N-heterocycles). Thus we decided to study the hydro-
based on group IV metal catalysts,2 lots of metal catalytic amination of terminal alkynes with secondary aliphatic amines.15
systems have been reported to date for the hydroamination of
As part of our works on copper-catalyzed reactions,16 herein
alkynes.3 More precisely, recently gold-catalyzed hydroamination we report a regioselective access to tertiary aliphatic amines via a
of alkynes exhibited interesting activities starting from a wide formation of C–N and C–H bonds relative to a hydroamination-
range of N-containing compounds such as ammonia,4 hydra- type intermediate (enamine), and then reduction of the latter
zine,5 aromatic amines,6 and aliphatic amines.7 Rhodium- (Scheme 1). The formation of the E-enamine, which occurs with
catalyzed anti-Markovnikov hydroamination of terminal alkynes the anti-Markovnikov addition of secondary amines, is the first
with primary and secondary amines has also been reported in example of a copper-catalyzed intermolecular hydroamination of
2007.8 On the other hand, the use of iridium-based catalysts with terminal alkynes with aliphatic amines.15,17
P,N-ligands undergoes Markovnikov addition of aromatic amines
We started our study by performing the model reaction of
across the triple bond of terminal alkyne.9 The Markovnikov phenyacetylene with dipropylamine. An excess of the latter was
product could also been obtained by using cationic palladium used in the presence of catalytic amounts of various copper
catalysts, starting from phenylacetylene and secondary aliphatic sources without any additive ligand in different solvents under
amines.10 Although these metals exhibit high catalytic activities nitrogen (Table 1). First attempts showed that 15 mol% of
for the hydroamination of alkynes, their potential of industrial CuCN in NMP (N-methyl-pyrrolidinone) afforded the most
applications at large scale is limited due to their expensive cost.
Copper-based catalysts could offer an alternative for this trans-
formation, and several systems were published these recent years.
a
´
Ecole Nationale Superieure de Chimie de Montpellier, Institut Charles Gerhardt,
CNRS UMR 5253, AM2N, 8 rue de l’Ecole Normale, 34296 Montpellier Cedex 05,
France. E-mail: marc.taillefer@enscm.fr, florian.monnier@enscm.fr
b
´
Laboratoire de Chimie, Institut Superieur d’Education et de Formation Continue,
´
43 Rue de la Liberte, 2019, Le Bardo, Tunisia
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Sequential Cu-catalyzed hydroamination/reduction.
c5cc02677f
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Table 1 Hydroamination of phenylacetylene with dipropylaminea
Amine
(n eq.)
Solvent
1 mL
3ab
(%)
4ab
(%)
5ab
(%)
6ab
(%)
Entry
[Cu]
1
2
3
4
5
6
7
8
None
CuCl
CuI
Cu2O
5
5
5
5
5
5
5
5
5
5
4
3
2
1
5
NMP
NMP
NMP
NMP
NMP
NMP
DMF
DMA
DMSO
Toluene
NMP
NMP
NMP
NMP
none
9
40
37
20
27
80
52
48
35
25
72
55
44
33
90
0
17
17
12
7
20
18
16
17
18
15
10
9
0
23
19
11
17
0
25
31
27
27
0
0
15
15
5
0
0
5
5
11
0
0
Cu(acac)2
CuCNc
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
9
10
11
12
13
14
15
Scheme 2 Hydroamination of phenylacetylene with various secondary
aliphatic amines. a Hydroamination performed with 0.15 mmol of CuCN
(15 mol%), 1 mmol of phenylacetylene, 5 equiv. of amine at 120 1C for 8 h,
unless otherwise noted. b NMR yield in % of enamines 3a–3j determined
using 1,3,5-trimethoxybenzene as internal standard, ratio in brackets are
the proportion of products 3/5. c Isolated yields of amines 7a–7j calculated
from 1 mmol of phenylacetylene. d Reaction performed on 10 mmol scale
without loose of yields and selectivities.
13
12
15
5
5
10
10
0
12
5
a
Performed with 0.15 mmol of [Cu] (15 mol%), 1 mmol of phenylacetyl-
ene, n equiv. of dipropylamine, 1 mL solvent at 120 1C for 8 h, unless
otherwise noted. GC yield in % determined using 1,3,5-trimethoxy-
benzene as internal standard. When using 5, 10 and 20 mol% of
b
c
CuCN, yields dropped respectively to 45, 60 and 75%.
with 2 equivalents of NaBH3CN and AcOH in dichloromethane
efficient and selective results, as we only observed the forma- during 24 h at room temperature under air atmosphere.7b,19 The
tion of 80% of an E-enamine (3a) resulting from the anti- corresponding tertiary amines 7a–7j were isolated in almost
Markovnikov addition and 20% of acetophenone 4a (Table 1, quantitative yields relative to the E-enamines. A wide range of
entry 6). The latter is probably formed from the degradation of homobenzylic amines was obtained in a one-pot two-step protocol
Markonikov-type enamine 5a, also observed under different starting from phenylacetylene and symmetrical (Scheme 2, 7a–7b,
experimental conditions (Table 1). All the other tested copper 7f–7h, 7j) and unsymmetrical secondary amines (Table 2, 7c–7e
sources afforded a low-selective mixture of products (Table 1, and 7i). This reaction was also efficient in one-gram scale as we
entries 2–5). Indeed in addition to 3a and 4a, we also observed did not observed any loss of yields and selectivities for the
the precursor of the latter (enamine 5a) and dienamine 6a.15 synthesis of 7g. It is noteworthy that there were no observed
Different other solvents were tested (Table 1, entries 7–10), but reactions with aliphatic alkynes and/or aromatic amines.
NMP was the most adequate one for this transformation. We
In a second set of experiments, we demonstrated that the
also demonstrated that 5 equivalents of dipropylamine were hydroamination-reduction sequence could be also applied for
optimum for a good formation rate of 3a (Table 1, entries 11–14). cyclic secondary amines (Scheme 3). Starting from azepine,
Following this observation, we tested this reaction without any piperidine and its derivatives, this simple methodology is effi-
solvent (Table 1, entry 15), and surprisingly it appeared that 3a cient and selective with again the anti-Markovnikov products
was obtained in even higher selectivity and yields. Thus, the best obtained 7k–7o.
conditions to perform efficiently the hydroamination are the
following: 1 equivalent of phenylacetylene reacts with dipropylamine
(in excess, 5 equivalents) during 8 h at 120 1C (Table 1, entry 15). It is
also worthy to underline that this original and simple copper-
catalyzed hydroamination of alkynes is a ligand-free process.
Following the initial success of this method, we tested various
symmetrical and unsymmetrical secondary aliphatic amines
under optimized conditions. As reported in Scheme 2, we were
able to observe the formation of E-enamines 3a–3j in good to
excellent yields.17 The latter were determined by 1H NMR relative
to an internal standard because our attempts to isolate 3a–3j by
Scheme 3 Hydroamination of phenylacetylene with secondary cyclic amines.
a Hydroamination performed with 0.15 mmol of CuCN (15 mol%), 1 mmol of
column chromatography afforded the corresponding degradation
phenylacetylene, 5 equiv. of amine at 120 1C for 8 h in absence of solvent.
product by hydrolysis.18 Then we reduced directly the enamines b Isolated yields amines 7k–7o calculated from 1 mmol of phenylacetylene.
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Table 2 Hydroamination of various arylacetylenes with dipropylaminea
3 (a) F. Alonso, I. P. Beletskaya and M. Yus, Chem. Rev., 2004,
104, 3079; (b) R. Severin and S. Doye, Chem. Soc. Rev., 2007,
36, 1407; (c) T. E. Mu¨ller, K. C. Hultzsch, M. Yus, F. Foubelo and
M. Tada, Chem. Rev., 2008, 108, 3795; (d) L. L. Schafer, J. C. H.
Yim and N. Zonson, Metal-catalyzed Cross-coupling Reactions
and More, Wiley-VCH, 1st ed., 2014, 1135; (e) L. Huang, M. Arndt,
K. Gooßen, H. Heydt and L. Gooßen, Chem. Rev., 2015, 115,
2596.
4 (a) V. Lavallo, G. D. Frey, B. Donnadieu, M. Soleilhavoup and
G. Bertrand, Angew. Chem., Int. Ed., 2008, 47, 5224; (b) G. Kovas,
A. Lledos and G. Ujaque, Angew. Chem., Int. Ed., 2011, 50, 11147.
5 (a) R. Kinjo, B. Donnadieu and G. Bertrand, Angew. Chem., Int. Ed.,
2011, 50, 5560; (b) M. J. Lopez-Gomez, D. Martin and G. Bertrand,
Chem. Commun., 2013, 49, 4483.
6 (a) E. Mizushima, T. Hayashi and M. Tanaka, Org. Lett., 2003, 5, 3350;
(b) A. Leyva and A. Corma, Adv. Synth. Catal., 2009, 351, 2876;
(c) H. Duan, S. Sengupta, J. L. Petersen, N. G. Akhmedov and X. Shi,
J. Am. Chem. Soc., 2009, 131, 12100; (d) E. Alvarado, A. C. Badaj,
T. G. Larocque and G. G. Lavoie, Chem. – Eur. J., 2012, 18, 12112.
7 (a) X. Zeng, G. D. Frey, S. Kousar and G. Bertrand, Chem. – Eur. J.,
2009, 15, 3056; (b) K. D. Hesp and M. Stradiotto, J. Am. Chem. Soc.,
2010, 132, 18026; (c) R. J. Lundgren, K. D. Hesp and M. Stradiotto,
Synlett, 2011, 2443.
Entry
R
Enamine, yieldsb (%)
Products, yieldsc (%)
1
2
3
4
5
6
7
8
4-Me
3-Me
4-tBu
4-Br
3p, 67
3q, 82
3r, 73
3s, 96
3t, 79
3u, 91
3v, 69
3w, 84
7p, 60
7q, 78
7r, 70
7s, 90
7t, 73
7u, 85
7v, 60
7w, 80
4-F
4-CO2Me
4-SMe
1-Naphthyl
a
Hydroamination performed with 0.15 mmol of CuCN (15 mol%),
1 mmol of arylacetylene, 5 equiv. of dipropylamine at 120 1C for 8 h.
8 (a) Y. Fukumoto, H. Asai, M. Shimizu and N. Chatani, J. Am. Chem.
Soc., 2007, 129, 13792; (b) C. Alonso-Moreno, F. Carrillo-Hermosilla,
J. Romero-Fernandez, A. M. Rodriguez, A. Otero and A. Antinolo,
Adv. Synth. Catal., 2009, 351, 881.
b
NMR yield in % determined using 1,3,5-trimethoxybenzene as inter-
c
nal standard. Isolated yields amines 7p–7w calculated from 1 mmol of
phenylacetylene.
9 R. Y. Lai, K. Surekha, A. Hayashi, F. Ozawa, Y. H. Liu, S. M. Peng and
S. T. Liu, Organometallics, 2007, 26, 1062.
10 A. R. Shaffer and J. A. R. Schmidt, Organometallics, 2008, 27,
1259.
Finally, we varied the source of arylacetylene (Table 2) and the
corresponding products 7p–7w were isolated with moderate to very
good yields. This copper-catalyzed transformation is tolerant with
respect to arylacetylenes substituted by electron-donating groups
(Table 2, entries 1–3 and 7), halogen atoms (entries 4 and 5), and
electron-withdrawing groups (entry 6). 1-Naphthylacetylene was
also transformed in its corresponding amine in 80% yield (entry 8).
This novel method is selective, nevertheless the mechanism is
not yet elucidated. Based on literature, four types of mechanism
for late-transition metal-catalyzed hydroamination of alkynes are
accepted.3e The first one relates to the addition of N-nucleophile on
a metal vinylidene intermediate, and the second one is the forma-
tion of M–H in the presence of acidic sources. Another possible
pathway is the oxidative addition of the metal to the N–H. Finally
the last postulated mechanism is the electrophilic activation of the
triple bond by the metal catalyst, acting as a lewis-acidic catalyst.
Although we do not have any evidence, we think that this trans-
formation could happen via the latter mechanism. Further studies
on the mechanism and the selectivity are in progress.
11 (a) S. M. Kumbar, T. Joseph and S. B. Halligudi, J. Mol. Catal. A:
Chem., 2005, 236, 139; (b) G. V. Shanbhag, S. M. Kumbar, T. Joseph
and S. B. Halligudi, Tetrahedron Lett., 2006, 47, 141; (c) Cu(II) ion-
exchange AISBA could also been used, see: G. V. Shanbhag,
T. Joseph and S. B. Halligudi, J. Catal., 2007, 250, 274(d) N. Pasha,
N. S. Babu, K. T. V. Rao, P. S. S. Prasad and N. Lingaiah, Tetrahedron
Lett., 2009, 50, 239–242.
12 M. Joshi, R. Tiwari and A. K. Verma, Org. Lett., 2012, 14, 1106.
13 D. W. Robbins and J. H. Hartwig, Science, 2011, 333, 1423.
14 (a) R. Sakae, K. Hirano, T. Satoh and M. Miura, Chem. Lett.,
2013, 42, 1128; (b) S.-L. Shi and S. L. Buchwald, Nat. Chem., 2015,
7, 38.
15 Recently we reported the CuCl-catalyzed one-pot Markovnikov
hydroamination and C-C coupling from two alkynes and cyclic
amines affording dienamines as described here: J. Bahri, B. Jamoussi,
A. van Der Lee, M. Taillefer and F. Monnier, Org. Lett., 2015, 17,
1224.
16 (a) H. J. Cristau, P. P. Cellier, J.-F. Spindler and M. Taillefer, Chem. –
Eur. J., 2004, 10, 5607; (b) M. Taillefer, N. Xia and A. Ouali, Angew.
Chem., Int. Ed., 2007, 46, 934; (c) F. Monnier and M. Taillefer, Angew.
Chem., Int. Ed., 2009, 48, 6954; (d) A. Tlili, F. Monnier and M. Taillefer,
Chem. – Eur. J., 2010, 16, 12299; (e) E. Racine, F. Monnier, J. P. Vors
and M. Taillefer, Org. Lett., 2011, 13, 2818; ( f ) A. Tlili, F. Monnier and
M. Taillefer, Chem. Commun., 2012, 48, 6408; (g) G. Danoun, A. Tlili,
F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2012, 51, 12815;
(h) E. Racine, F. Monnier, J. P. Vors and M. Taillefer, Chem. Commun.,
2013, 49, 7412; (i) F. Monnier and M. Taillefer, Top. Organomet.
In summary, we have discovered the first copper-catalyzed inter-
molecular hydroamination of terminal alkynes with secondary
aliphatic amines, affording anti-Markovnikov E-enamines. The latter
are easily reduced in high yields in amines which are major targets
in healthcare. Furthermore this simple, selective and highly efficient
catalytic system proceeds in solvent and ligand-free conditions.
`
Chem., 2013, 46, 173; ( j) G. Lefevre, A. Tlili, M. Taillefer, C. Adamo,
I. Ciofini and A. Jutand, Dalton Trans., 2013, 42, 5348; (k) J. Ballester,
J. Gatignol, G. Schmidt, C. Alayrac, A.-C. Gaumont and M. Taillefer,
ChemCatChem, 2014, 6, 1549.
17 The stereo- and regiochemistry of the E-enamines were supported by
1H NMR of enamine prior to their reduction. For more details, see
experimental section with the description of enamine 3x. This
enamine has been isolated from 2-pyridineacetylene.
18 S. Fleischer, S. Werkmeister, S. Zhou, K. Junge and M. Beller,
Chem. – Eur. J., 2012, 18, 9005.
Notes and references
1 S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54, 3451.
2 (a) P. J. Walsh, F. J. Hollander and R. G. Bergman, J. Am. Chem. Soc.,
1988, 110, 8729; (b) P. J. Walsh, A. M. Baranger and R. G. Bergman, 19 J. C. H. Yim, J. A. Bexrud, R. O. Ayinla and L. L. Schafer, J. Org.
J. Am. Chem. Soc., 1992, 114, 1708.
Chem., 2014, 79, 2015.
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Chem. Commun.