N-heterocyclic carbene (NHC)-copper(I) complexes as catalysts for A 3 reactions

Article abstract of DOI:10.1055/s-0033-1338944

The use of easily synthesized NHC-Cu(I) complexes for the preparation of a variety of propargylamines through an A³ coupling scheme is described. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338944

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N-Heterocyclic Carbene (NHC)–Copper(I) Complexes as Catalysts for A
Reactions
Catalytic Multicomponent Reactions
Ming-Tsz Chen, Oscar Navarro*1
Department of Chemistry, University of Hawaii at Manoa, 2545 McCarthy Mall, Honolulu, HI 96825, USA
Fax +44(1273)876687; E-mail: o.navarro@sussex.ac.uk
Received: 04.03.2013; Accepted after revision: 19.04.2013
prepared NHC–Ag(I) complexes for this reaction,11 we
Abstract: The use of easily synthesized NHC–Cu(I) complexes for
decided to determine whether easily synthesized NHC–
CuCl complexes (Figure 1) would also display an en-
hancement of reactivity when compared to other copper
systems.
the preparation of a variety of propargylamines through an A3
coupling scheme is described.
Key words: N-heterocyclic carbine, copper, homogeneous cataly-
sis, multicomponent reaction, green chemistry
R
N
Creating a defined and elaborated structure from three or
more components in a single step is an exciting challenge,
pushing the limits of catalysis by breaking and creating
bonds in specific positions and in a specific sequence. Ide-
ally, these multicomponent reactions (MCR) should be
atom-efficient, robust, and user-friendly.2,3 A beautiful
example is the now widely used A3 coupling (Scheme 1),4
in which an aldehyde, and amine, and an alkyne are com-
bined to form a propargylamine in the presence of a cata-
lytic amount of a metal salt or organometallic complex. A
variety of metals have been used in this reaction, being
copper one of the most employed. In general, most of
these catalytic systems require of high catalyst loadings
(5–10 mol%) and high temperatures in combination with
long reaction times. While many times the catalyst is just
a copper salt,5 the use of ligands have proven to be bene-
ficial on the form of lower catalyst loadings or reaction
times. Ligands that have been employed include
imidazolines6 and pybox-type,7 among others.8
N
1A, R =
2A, R =
1B, R =
2B, R =
Cu
R
R
Cl
1
R
N
N
Cu
Cl
2
Figure 1 NHC–CuCl complexes used in this study
The synthesis of NHC–CuCl complexes is very straight-
forward and high-yielding. It can be performed in one sin-
gle step by combining, even in open air, the corresponding
imidazolium or imidazolinium salt and a copper source at
high temperature. For instance, our group recently report-
ed the use of microwave heating for these reactions in as
little as 30 minutes on a 1 mmol scale (1 h on a 5 mmol
scale).12 This allows for the synthesis of a library of cata-
lysts in a very short time, and even on an automated man-
ner. Conventional heating is as high-yielding, albeit
requiring longer reaction times.13
NR2R3
R4
catalyst
R1CHO + NHR2R3
+
R1
conditions
Our optimization process began by screening a variety of
solvents using 0.5 mol% of SIPr–CuCl (1a, Figure 1) as
catalyst. In all cases, the reactions were loaded in open air,
and the solvents were used in technical grade (nonde-
gassed, nonanhydrous). As for our NHC–Ag(I) system,
the use of MeOH led to the highest yield of the desired
propargylamine (Table 1). Increasing the catalyst loading
to 1 mol% derived in a higher yield in a shorter time.
R4
Scheme 1 The A3 reaction for the synthesis of propargylamines
Interestingly, the use of commonly used N-heterocyclic
carbenes (NHCs),9 either already coordinated to copper
on in an in situ manner, has been barely explored. To the
best of our knowledge, only one example has been report-
ed in the literature making use of NHC–Cu(I) catalysts for
this reaction, in which Wang et al. synthesized and used a
silica-immobilized complex prepared in three steps that
take more than three days.10 In addition, the A3 reactions
needed to be carried out under an inert atmosphere. Since
we recently reported on the excellent activity of easily
A comparison of different NHC–CuCl complexes fol-
lowed (Table 2). A clear difference in performance be-
tween ligands bearing 2,6-diisopropylphenyl as N-
substituents and those bearing mesityl groups can easily
be observed (1a and 2a vs. 1b and 2b), as well as a slightly
better performance by saturated ligands when compared
to the unsaturated counterparts (1a and 1b vs. 2a and 2b).
The presence of a larger halide seems to decrease the ac-
tivity of the complex as a catalyst for this reaction, since
an analogous iodo-bearing complex SIPr–CuI (3) per-
SYNLETT 2013, 24, 1190–1192
Advanced online publication: 10.05.2013
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DOI: 10.1055/s-0033-1338944; Art ID: ST-2013-R0198-C
© Georg Thieme Verlag Stuttgart · New York

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Catalytic Multicomponent Reactions
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With the optimized conditions, complex 1a proved to be
an efficient catalyst for this reaction when coupling ali-
phatic aldehydes (Scheme 2, compounds 4–13), affording
very good yields of a variety of propargylamines in short
times and at room temperature, with the exception of com-
pound 7. Interestingly and opposite to most copper-cata-
lyzed A3 systems in the literature, a dramatic decrease in
activity can be observed when the aldehyde is aromatic
(compounds 14–20). Higher catalyst loadings, higher re-
action temperatures (50–70 °C) and longer reaction times
(1–2 d) are required to obtain the desired products. This
switch in activity when NHC-bearing complexes are used
could be also observed in Wang’s communication.10 Un-
der these conditions, the desired propargylamines were
obtained in good to very good yields.
Table 1 Solvent Screening
O
H
N
1A
+
+ Ph
H
N
H
solvent
25 °C
Ph
Entry
Solvent
Conversion (%)a,b
1
2
neat
21
<5
13
29
7
acetone
CH2Cl2
MeCN
toluene
DMF
3
4
5
R2
R2
6
9
N
1A (n mol%)
R1CHO
+ R2R2NH +
O
R3
H
R1
7
H2O
6
MeOH
R3
8
i-PrOH
MeOH
MeOH
29
75
94
N
N
N
N
9
Cy
Cy
Cy
Cy
10c
a Reaction conditions: aldehyde (1.0 mmol), piperidine (1.1 mmol),
phenylacetylene (1.1 mmol), 1a (0.5 mol%), solvent (0.5 mL), 25 °C,
3 h.
Ph
Ph
Ph
Ph
4
6
7
5
n = 2, 3 h, 90%a
n = 1, 20 min, 94%
n = 1, 2 h, 94% n = 1, 5 h, 88%
b Conversion into product determined by GC (average of 2 runs).
c Conditions: 1a (1 mol%), 2 h.
Ph
N
N
Et
Et
N
N
Et
Ph
6
6
Et
forms slightly worse than the chloro counterpart (Table 2,
entry 5). This fact agrees with observations made in pre-
vious reports, in which it has been suggested that the first
step of the catalytic cycle involves the coordination of the
alkyne to the complex, followed by the formation of the
corresponding metal alkynide.11,14
Ph
Ph
Ph
Ph
8
9
10
11
n = 1, 1 h, 94% n = 1, 4 h, 91%
n = 1, 1 h, 99%
n = 1, 2 h, 97%
Cy
N
Cy
N
N
Table 2 Catalyst Screening
12
13
n = 1, 2 h, 91%
n = 1, 5 h, 61%
O
O
N
complex
H
+
+ Ph
H
N
N
N
N
N
H
MeOH
25 °C
Ph
Ph
Ph
Ph
Ph
Entry
Complex
Conversion (%)a,b
Ph
Ph
Ph
Ph
2
14
15
16
17
n = 3, 24 h, 90%a n = 3, 48 h, 88%b n = 3, 48 h, 85%b n = 3, 48 h, 79%b
1
2
3
4
5
1a
2a
1b
2b
3
94
82
7
N
N
N
OMe
Cl
4
Ph
Ph
Ph
n = 3, 24 h, 88%a
90
18
19
n = 3, 16 h, 90%b
20
n = 3, 16 h, 87%b
a Reaction conditions: aldehyde (1.0 mmol), piperidine (1.1 mmol),
phenylacetylene (1.1 mmol), complex (1 mol%), MeOH (0.5 mL),
25 °C.
Scheme 2 Substrate scope. Reagents and conditions: aldehyde (1.0
mmol), amine (1.1 mmol), alkyne (1.1 mmol), 1a (n mol%), MeOH
(0.5 mL), 25 °C; the yield is the average of 2 runs. a Reaction carried
out at 50 °C. b Reaction carried out at 70 °C.
b Conversion into product determined by GC (average of 2 runs).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1190–1192

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M.-T. Chen, O. Navarro
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(2) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
In conclusion, we have described the development of a
user-friendly NHC–CuCl-catalyzed A3 reaction. The re-
actions can be set up on a bench without the need of anhy-
drous solvents or inert atmosphere. The use of these easily
synthesized complexes as catalysts for the coupling of a
wide range of aliphatic aldehydes at room temperature
and in short reaction times has been shown. Higher cata-
lyst loadings and longer reaction times are required for the
coupling of aromatic aldehydes.
Wiley-VCH: Weinheim, 2005.
(3) Some recent reviews on MCR: (a) Ruitjer, E.; Scheffelaar,
R.; Orru, R. V. A. Angew. Chem. Int. Ed. 2011, 50, 6234.
(b) Ganem, B. Acc. Chem. Res. 2009, 42, 463. (c) Ramón, D.
J.; Yus, M. Angew. Chem. Int. Ed. 2005, 44, 1602.
(4) Yoo, W.-J.; Zhao, L.; Li, C.-J. Aldrichimica Acta 2011, 44,
43.
(5) (a) Meyet, C. E.; Pierce, C. J.; Larsen, C. H. Org. Lett. 2012,
4, 964. (b) Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang, F.-M.; Fan,
C.-A. Org. Lett. 2004, 6, 1001.
(6) Nakamura, S.; Ohara, M.; Nakamura, Y.; Shibata, N.; Toru,
T. Chem. Eur. J. 2010, 16, 2360.
General Procedure for A3 Reactions
All reactions were set up in air. The catalyst (n mol%) was added to
a vial equipped with a magnetic bar, followed by the aldehyde (1
mmol), amine (1.1 mmol), alkyne (1.1 mmol), and solvent (0.5 mL).
The vial was closed with a screw cap fitted with a septum and the
mixture was allowed to stir on a stirring plate at the corresponding
temperature. The reaction was monitored by gas chromatography.
When it was determined that the reaction was finished, the solvent
was evaporated in vacuo and the product isolated by flash chroma-
tography. The amount of product shown is the average of two
runs.15
(7) Bisai, A.; Singh, V. A. Org. Lett. 2006, 8, 2405.
(8) Knöpfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
Carreira, E. M. Angew. Chem. Int. Ed. 2004, 43, 5971.
(9) (a) Heterocyclic Carbenes in Transition Metal Catalysis and
Organocatalysis; Cazin, C. S. J., Ed.; Springer: London,
2010. (b) N-Heterocyclic Carbenes in Transition Metal
Catalysis; Glorius, F., Ed.; Springer: Berlin, 2007.
(10) Wang, M.; Li, P.; Wang, L. Eur. J. Org. Chem. 2008, 2255.
(11) Chen, M.-T.; Landers, B.; Navarro, O. Org. Biomol. Chem.
2012, 10, 2206.
(12) Landers, B.; Navarro, O. Eur. J. Inorg. Chem. 2012, 2980.
(13) Citadelle, C. A.; Nouy, E. L.; Bisaro, F.; Slawin, A. M. Z.
Dalton Trans. 2010, 39, 4489.
Acknowledgment
(14) Li, Y.; Chen, X.; Song, Y.; Fanf, L.; Zou, G. Dalton Trans.
2011, 40, 2046.
(15) Representative Example: 1-(1-Cyclohexyl-3-phenyl-2-
propynyl)piperidine (4)
The National Science Foundation (CHE 0924324) is gratefully ack-
nowledged for support.
1H NMR (300 MHz, CDCl3): δ = 0.89–1.11 (m, 2 H), 1.15–
1.35 (m, 3 H), 1.45–1.50 (m, 2 H), 1.57–1.72 (m, 6 H), 1.78–
1.82 (m, 2 H), 2.05–2.17 (m, 2 H), 2.40–2.46 (m, 2 H), 2.63–
2.70 (m, 2 H), 3.13 (d, J = 9.9 Hz, 1 H), 7.29–7.35 (m, 3 H),
7.45–7.48 (m, 2 H). 13C{1H} NMR (75 MHz, CDCl3): δ =
26.7, 26.1, 26.3, 26.8, 30.4, 31.3, 39.6, 64.3, 86.1, 87.7,
123.8, 127.5, 128.1, 131.7..
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
(1) Current address: Department of Chemistry, University of
Sussex, Brighton, BN1 9QJ, UK.
Synlett 2013, 24, 1190–1192
© Georg Thieme Verlag Stuttgart · New York