Unprecedented Cu(I)-catalyzed microwave-assisted three-component coupling of a ketone, an alkyne, and a primary amine

Article abstract of DOI:10.1021/ol1008312

An efficient, microwave-assisted Cu(I)-catalyzed one-pot coupling of a ketone, an alkyne, and a primary amine (KA² coupling) is described, giving access to secondary propargylamines.

Full text of DOI:10.1021/ol1008312

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2638-2641
Unprecedented Cu(I)-Catalyzed
Microwave-Assisted Three-Component
Coupling of a Ketone, an Alkyne, and a
Primary Amine
Olga P. Pereshivko, Vsevolod A. Peshkov, and Erik V. Van der Eycken*
Laboratory for Organic & MicrowaVe-Assisted Chemistry (LOMAC),
Department of Chemistry, Katholieke UniVersiteit LeuVen, Celestijnenlaan 200F,
B-3001 LeuVen, Belgium
erik.Vandereycken@chem.kuleuVen.be
Received April 12, 2010
ABSTRACT
An efficient, microwave-assisted Cu(I)-catalyzed one-pot coupling of a ketone, an alkyne, and a primary amine (KA2 coupling) is described,
giving access to secondary propargylamines.
Propargylamines are widely used as intermediates for the
synthesis of various nitrogen-containing biologically active
compounds and natural products.1 The three-component
coupling of an aldehyde, an alkyne, and an amine, commonly
called A3 coupling, is a convenient and general approach to
propargylamines.2 The scope of this three-component reac-
tion has been explored under various conditions.3 Different
examples of asymmetric variants have also been reported.4
A tentative mechanism of the A3 coupling involves C-H
activation of the alkyne by a metal catalyst.3b,d,f The in situ
generated metal acetylide reacts with the iminium ion arising
from the aldehyde and the amine, resulting in the formation
of the propargylamine with concomitant regeneration of the
catalyst. The reaction of an imine5 or an enamine6 with an
alkyne in the presence of a suitable catalyst leads to the same
result. Moreover, the enantioselective addition of a terminal
alkyne to an imine or enamine provides access to optically
pure propargylamines.5,7
Despite the huge advancements, A3-coupling reactions
were mainly optimized for anilines and secondary amines
resulting in the formation of N-arylpropargylamines or
(1) (a) Kauffman, G. S.; Harris, G. D.; Dorow, R. L.; Stone, B. R. P.;
Parsons, R. L.; Pesti, J. A.; Magnus, N. A.; Fortunak, J. M.; Confalone,
P. N.; Nugent, W. A. Org. Lett. 2000, 2, 3119. (b) Huffman, M. A.; Yasuda,
N.; DeCamp, A. E.; Grabowski, E. J. J. Org. Chem. 1995, 60, 1590. (c)
Nilsson, B.; Vargas, H. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem. 1992,
35, 285. (d) Hattoi, K.; Miyata, M.; Yamamoto, H. J. Am. Chem. Soc. 1993,
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(4) (a) Gommermann, N.; Knochel, P. Chem. Commun. 2004, 2324. (b)
Gommermann, N.; Knochel, P. Chem. Commun. 2005, 4175. (c) Bisai, A.;
Singh, N. V. Org. Lett. 2006, 8, 2405. (d) Gommermann, N.; Knochel, P.
Chem.sEur. J. 2006, 12, 4380
(5) (a) Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319. (b) Jiang,
B.; Si, Y. G. Tetrahedron Lett. 2003, 44, 6767
.
(2) For reviews, see: (a) Wei, C.; Zhang, L.; Li, C. J. Synlett 2004, 1472.
(b) Zani, L.; Bolm, C. Chem. Commun. 2006, 4263.
.
(6) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002,
(3) (a) Dyatkin, A. B.; Rivero, R. A. Tetrahedron Lett. 1998, 39, 3647.
(b) Li, C. J.; Wei, C. Chem. Commun. 2002, 268. (c) Leadbeater, N. E.;
Torenius, H. M.; Tye, H. Mol. DiVers. 2003, 7, 135. (d) Wei, C.; Li, Z.; Li,
C. J. Org. Lett. 2003, 23, 4473. (e) Ju, Y.; Li, C. J.; Varma, R. S. QSAR
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1315.
41, 2535
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(7) (a) Wei, C.; Li, C. J. J. Am. Chem. Soc. 2002, 124, 5638. (b)
Benaglia, M.; Negri, D.; Dell’Anna, G. Tetrahedron Lett. 2004, 45, 8705.
(c) Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143. (d) Colombo,
F.; Benaglia, M.; Orlandi, S.; Usuelli, F.; Celentano, G. J. Org. Chem. 2006,
71, 2064
.
10.1021/ol1008312  2010 American Chemical Society
Published on Web 05/04/2010

Table 1. Optimization of the KA2-Coupling Conditionsa
entry
1a/2a/3a (mmol)
cat. (mol %)
time (min)
conditions
yieldb (%)
1
2
3
4
5
6
7
8
9
1:1.2:1.2
1:1:1.2
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (10)
CuBr (20)
25
25
25
25
25
25
20h
15
25
25
neat, MW, 100 °C
neat, MW, 100 °C
neat, MW, 100 °C
neat, MW, 80 °C
neat, MW, 120 °C
toluene, MW, 100 °C
toluene, conv, 100 °C
neat, MW, 100 °C
neat, MW, 100 °C
neat, MW, 100 °C
51c
61
76
43
62
54
59
54
63
72
1.2:1:1.2
1.2:1:1.2
1.2:1:1.2
1.2:1:1.2
1.2:1:1.2
1.2:1:1.2
1.2:1:1.2
1.2:1:1.2
10
a When the reaction was run under microwave irradiation a maximum power of 80 W was used. b Isolated yields based on 4-methoxybenzylamine.
c Isolated yield based on cyclohexanone.
tertiary propargylamines. Primary amines are considered as
being difficult substrates thus, limiting access to secondary
propargylamines.8 However, these amines are potent syn-
thetic intermediates for the synthesis of pyrroles,9 quino-
lines,10 and oxazolidinones.11 Recently, we have reported
an optimized protocol for the synthesis of secondary alky-
lpropargylamines via a microwave-assisted A3-coupling
reaction.12 We were rather surprised to found that the
aldehyde could be replaced by a ketone in this process,
as to the best of our knowledge, there are no examples in
the literature describing the application of ketones in the
A3 coupling. Herein, we report an unprecedented Cu(I)-
catalyzed coupling of a ketone, an alkyne, and a primary
amine. We will call this novel three-component reaction
a KA2 coupling.
(Table 1, entry 5). Solventless conditions proved to be most
suitable for the reaction as the use of toluene resulted in a
substantially decreased yield of 54% (Table 1, entry 6). When
the reaction in toluene was conducted under conventional
heating at the same temperature, the desired propargylamine
4a was obtained in a comparable moderate yield of 59%
after an extended reaction time of 20 h (Table 1, entry 7). A
shorter irradiation time of 15 min (Table 1, entry 8) or a
diminished concentration of the CuI catalyst to 10 mol %
(Table 1, entry 9) all resulted in lower yields. The application
of CuBr instead of CuI delivered compound 4a in a
comparable yield (Table 1, entries 3 and 10).
The scope of the reaction was evaluated for various
ketones, primary amines, and alkynes applying the optimal
conditions (Table 1, entry 3). Both aromatic and aliphatic
alkynes were explored as reaction partners, but the last
afforded the target compounds 4e,f only in low to moderate
yields (Table 2, entries 5 and 6), even when 2 equiv of alkyne
was used. To expand the scope of the protocol, a variety of
primary amines was evaluated. All reactions seemed to be
working well when 6-membered (hetero)cyclic ketones were
used. When cyclohexanone (1a) was used, the desired
compounds 4a-d,g-l were obtained in 46-82% yield
(Table 2, entries 1-4 and 7-12). When N-protected pip-
eridinones 1b-e were used, yields between 38% and 82%
were obtained (Table 2, entries 13-16). 2-Methylcyclohex-
anone (1f) delivered the adducts 4q (mixture of diastereomers
(10:1)) in only 33% yield (Table 2, entry 17), clearly showing
that sterical hindrance might play an important role for the
yield of the reaction. The fact that 3-methylcyclohexanone
(1g) is working well (Table 2, entry 18) confirms this
conclusion. It seemed that also conformational factors are
playing a crucial role in this process, as when cycloheptanone
(1h) was used the yield dropped to 21% (Table 2, entry 19).
It is probably that ketimines from 6-membered (hetero)cyclic
ketones (see the mechanism bellow) are more accessible for
The reaction conditions of the KA2 coupling were opti-
mized using cyclohexanone 1a, 4-methoxybenzylamine 2a,
and phenylacetylene 3a (Table 1). When a (1:1.2:1.2) mixture
of the respective compounds together with 20 mol % of CuI
catalyst was irradiated under solventless conditions at a
ceiling temperature of 100 °C and a maximum power of 80
W for 25 min, the desired propargylamine 4a could be
isolated in 51% yield (Table 1, entry 1). Changing the relative
amounts of the three components it was found that the
optimal ratio was (1.2:1:1.2) providing the desired compound
in 76% yield (Table 1, entries 1-3). A lower reaction
temperature of 80 °C reduced the yield of the propargylamine
4a to 43% (Table 1, entry 4), while increasing the temper-
ature to 120 °C also resulted in a decreased yield of 62%
due to the formation of several unidentified byproducts
(8) (a) Giles, R. L.; Sullivan, J. D.; Steiner, A. M.; Looper, R. E. Angew.
Chem., Int. Ed. 2009, 48, 3116. (b) Mont, N.; Mehta, V. P.; Appukkuttan,
P.; Beryozkina, T.; Toppet, S.; Van Hecke, K.; Van Meervelt, L.; Voet,
A.; DeMaeyer, M.; Van der Eycken, E. V. J. Org. Chem. 2008, 73, 7509.
(9) Bremner, W. S.; Organ, M. G. J. Comb. Chem. 2008, 10, 142.
(10) Kuninobu, Y.; Inoue, Y.; Takai, K. Chem. Lett. 2007, 36, 1422.
(11) Yoo, W. J.; Li, C. J. AdV. Synth. Catal. 2008, 350, 1503.
(12) Bariwal, J. B.; Ermolat’ev, D. S.; Van der Eycken, E. V.
Chem.sEur. J. 2010, 16, 3281.
Org. Lett., Vol. 12, No. 11, 2010
2639

Table 2. Scope and limitations of the KA2 Couplinga
a A mixture of amine 1 (1.0 mmol), alkyne 2 (1.2 mmol), ketone 3 (1.2 mmol), and CuI (20 mol %) was irradiated at a ceiling temperature of 100 °C
and a maximum power of 80 W for 25 min. b Isolated yields are reported. c 2 mmol of alkyne was used.
copper acetylide attack than imines from other ketones.13
Remarkably, the reaction with acetone (1i) resulted in a low
yield of 30% (Table 2, entry 20).
for A3-coupling reactions compared to secondary amines,
results in the formation of synthetically useful secondary
alkylpropargylamines. Therefore, this KA2 coupling can be
A tentative mechanism for the KA2 coupling is proposed
in Scheme 1. The copper catalyst reacts with the alkyne to
form the copper acetylide. The in situ formed imine is
attacked by the copper acetylide (transitions state A),
resulting in the copper-complexed intermediate B. Decom-
plexation produces the free propargylamine 4 and regenerates
the Cu(I) catalyst.
Scheme 1
.
Proposed Mechanism for the KA2 Coupling
In conclusion, we have developed a novel Cu(I)-catalyzed,
microwave-assisted, three-component coupling of a ketone,
an alkyne, and a primary amine, called a KA2-coupling
reaction. The replacement of an aldehyde for a ketone in
the A3 coupling is unprecedented. Moreover, the application
of primary amines, known to be difficult reaction partners
(13) For the addition of lithium acetylides and n-BuLi to six-membered
ketimines, see: Ma, Y.; Lobkovsky, E.; Collum, D. B. J. Org. Chem. 2005,
70, 2335.
2640
Org. Lett., Vol. 12, No. 11, 2010

regarded as a welcome additional method for the generally
applied A3-coupling reaction.
Supporting Information Available: Representative ex-
perimental procedure and characterization of all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Support was provided by the Research
Fund of the Katholieke Universiteit Leuven and by the FWO
(Fund for Scientific Research, Flanders, Belgium). V.A.P.
is grateful to the Katholieke Universiteit Leuven for a
predoctoral scholarship.
OL1008312
Org. Lett., Vol. 12, No. 11, 2010
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