Redox-neutral copper(II) carboxylate catalyzed α-alkynylation of amines

Article abstract of DOI:10.1002/anie.201300021

Cocktail of three: A new strategy for iminium ion isomerization was applied to the direct, redox-neutral α-alkynylation of amines. Copper(II) 2-ethylhexanoate [Cu(2-EH)₂] was identified as the optimal catalyst for this three-component coupling reaction of secondary amines, aldehydes, and alkynes. MW=microwave. Copyright

Full text of DOI:10.1002/anie.201300021

Angewandte
Chemie
DOI: 10.1002/anie.201300021
À
C H Functionalization
Redox-Neutral Copper(II) Carboxylate Catalyzed a-Alkynylation of
Amines**
Deepankar Das, Aaron X. Sun, and Daniel Seidel*
Propargylic amines represent important building blocks,[1]
and compounds of this class (e.g., 1) are readily assembled
by three-component reactions of amines, aldehydes, and
alkynes, frequently referred to as A3 reactions [Eq. (1)].[2–4]
Methods that enable direct access to the ring-substituted
isomers 2 are much more limited [see Eq. (2)]. As part of
a program to develop redox-neutral[5] reactions of broad
utility,[6] we recently reported an a-amino acid based decar-
boxylative three-component coupling strategy to access ring-
substituted propargylic amines such as 2 [Eq. (2)].[6e] A nearly
identical approach was also reported by Li et al.[7–9] Replace-
ment of the a-amino acid with a simple amine would
represent a significant advance [Eq. (3)]. Herein we report
the first examples of this elusive transformation.
amine a-alkynylation (Scheme 1). To realize such a process,
reaction conditions must be identified so as to prevent the
regular course of events in an A3 reaction, namely addition of
Scheme 1. Competing reaction pathways in the formation of isomeric
propargylic amines.
the metal acetylide to the initially formed iminium ion 3 to
give the undesired isomer 1. Access to 2 requires the
isomerization of the iminium ion 3 into 5, and must proceed
in the presence of the metal acetylide. This isomerization
could in principle be accomplished by iminium deprotona-
tion/reprotonation via the azomethine ylide intermediate 4.
In fact, a-deprotonation of iminium ions as a means to form
azomethine ylides has been reported in the context of
pericyclic azomethine ylide chemistry.[15,16] We have previ-
ously developed powerful reactions of azomethine ylides
À
À
leading to intramolecular C N and C C bond formation
through nonpericyclic pathways.[6,17] Upon considering poten-
tial solutions to the added challenge of performing amine a-
functionalizations in an intermolecular setting, we reasoned
that an electron-withdrawing group (R) on 3 would serve to
accelerate iminium isomerization through acidification of the
amine a-proton. In addition, increasing the steric demand of
R would be expected to slow down the rate of the formation
of 1.
Direct a-alkynylation of tertiary amines has previously
À
been accomplished by means of oxidative C H functionali-
zation,[10,11] including photoredox catalysis.[12] These methods
require stoichiometric amounts of oxidant and are often
limited to N-aryl tetrahydroisoquinolines and N,N-dialkylani-
lines.[13,14] As an attractive alternative, we envisioned a direct,
redox-neutral, three-component coupling with concurrent
With the above considerations in mind and encouraged by
our recent success in developing a redox-neutral amine a-
cyanation,[6m] we selected 2,6-dichlorobenzaldehyde as the
reaction partner in the proposed three-component reaction
with pyrrolidine and phenylacetylene (Table 1). Different
catalysts were evaluated as part of this survey, which was
conducted under microwave conditions. Using CuBr and
TMEDA, the catalyst combination that proved optimal in the
decarboxylative alkynylation [Eq. (2)],[6e] a 1:3 mixture of 6a
and 7a was obtained in 65% yield (entry 1). CuBr or CuBr2
provided higher overall yields, but less favorable product
ratios (entries 2 and 3). Interestingly, copper(II) triflate
provided a favorable 5:1 ratio of regioisomers, albeit in
moderate yield (entry 4). Gratifyingly, copper(II) acetate
gave a 7:1 ratio of regioisomers but without improvement in
[*] D. Das, A. X. Sun, Prof. Dr. D. Seidel
Department of Chemistry and Chemical Biology
Rutgers, The State University of New Jersey
Piscataway, NJ 08854 (USA)
E-mail: seidel@rutchem.rutgers.edu
Homepage: http://seidel-group.com/
[**] Financial support from the NIH-NIGMS (R01GM101389-01) is
gratefully acknowledged. Partial support (microwave purchase) was
provided by the National Science Foundation (Grant CHE-
0911192). A.X.S. acknowledges support from the Aresty Research
Center for Undergraduates and Rutgers University School of Arts
and Sciences. D.S. is a fellow of the Alfred P. Sloan Foundation and
the recipient of an Amgen Young Investigator Award.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300021.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Table 1: Evaluation of catalysts for the direct three-component a-
alkynylation.[a]
Entry
Catalyst
6a/7a
6a+7a
Yield [%]
1
2
3
4
5
6
7
8
CuBr + TMEDA (30 mol%)
CuBr
CuBr2
1:3
1:5
1:4
5:1
7:1
1:1
7:1
20:1
14:1
15:1
1:4
65
94
82
45
47
82
74
82
76
82
67
76
67
0
Cu(OTf)2
Cu(OAc)2·H2O
Cu(HCOO)2·H2O
Cu(OBz)2·H2O
copper(II) 2-ethylhexanoate
copper(II) cyclohexylbutanoate
copper(II) pivalate
[Cu(acac)2]
[Cu(hfacac)2]·H2O
Cu(NO2)2·H2O
2-ethylhexanoic acid
none
9
10
11
12
13
14
15
3:1
1:1
N/A
N/A
Scheme 2. Dependence of product ratios on the aldehyde. MW=
microwave.
0
[a] Reactions were performed on a 0.5 mmol scale with anhydrous
toluene. Yields are those of the isolated and chromatographically
purified compounds. acac=acetylacetonate, hfacac=hexafluoroacetyl-
acetonate, N/A=not applicable, TMEDA=N,N,N’,N’-tetramethylethy-
lenediamine.
3,4-dichlorobenzaldehyde. Unsubstituted benzaldehyde gave
rise to 6d and 7d in a 1:2 ratio, thus favoring the undesired
regioisomer. 2-Methylbenzaldehyde performed slightly
better, thus providing a 1:1.4 ratio of the products 6e and
7e. A comparison of the results obtained with benzaldehyde,
4-chlorobenzaldehyde, and 4-methoxybenzaldehyde (prod-
ucts 6d, 6 f, and 6g) clearly established the impact of
electronic factors on the regioselectivity, with the more
electron-poor aldehydes providing more favorable product
ratios. However, upon inspection of all results, it can be
concluded that steric factors outweigh electronics. The case in
point is mesitaldehyde which provided an excellent product
ratio of 11:1. Even the electron-rich 2,6-dimethoxybenzalde-
hyde provided a more favorable product ratio than benzal-
dehyde. In contrast, cyclohexane carbaldehyde gave rise to
almost none of the desired product but rather underwent the
standard A3 reaction. As a side note, the reaction of 2,6-
dichlorobenzaldehyde, pyrrolidine, and phenylacetylene can
be performed under reflux using otherwise identical reaction
conditions. In this instance, the products 6a and 7a were
isolated in a 19:1 ratio (86% yield) after a reaction time of
just 30 minutes.
The scope of the three-component coupling reaction was
explored under the optimized microwave conditions
(Scheme 3). Reactions of 2,6-dichlorobenzaldehyde, pyrroli-
dine, and various terminal alkynes resulted in the formation
of the desired products in generally good to excellent yields.
Aromatic, alkenyl, and aliphatic substituents on the alkyne
were readily accommodated. In the majority of cases,
products were obtained with regioselectivities exceeding
25:1. Importantly, the a-alkynylation is not limited to
pyrrolidine. Piperidine and azepane also underwent [Cu(2-
EH)2]-catalyzed couplings with various terminal alkynes to
provide propargylic amines in good to excellent yields. While
the observed regioselectivities for these more challenging
substrates are lower than that for pyrrolidine, they are still in
yield (entry 5). Other copper(II) carboxylate salts such as
copper(II) benzoate also yielded 6a as the major product.
Copper(II) carboxylates with enhanced solubilities provided
favorable product ratios and good product yields (entries 8–
10). Readily available copper(II) 2-ethylhexanoate [Cu(2-
EH)2] was identified as an excellent catalyst, thus allowing for
the isolation of 6a and 7a in a 20:1 ratio and 82% yield.
Notably, [Cu(acac)2] provided product ratios vastly different
from that of the corresponding perfluorinated catalyst
(entries 11 and 12). The desired products were neither
obtained with 2-ethylhexanoic acid (2-EHA) nor in the
absence of a catalyst. In all copper(II)-catalyzed reactions,
1,4-diphenylbuta-1,3-diyne, the corresponding Glaser cou-
pling product[18] of phenylacetylene was isolated as a byprod-
uct.
Upon further examination of the parameters, we found
that replacement of anhydrous toluene with HPLC grade
toluene had no deleterious effect on the outcome of the
reaction. Lowering the concentration from 0.5m to 0.25m was
found to be beneficial. Under these reaction conditions, the
reaction of 2,6-dichlorobenzaldehyde, pyrrolidine, and phe-
nylacetylene gave products 6a and 7a in a greater than 25:1
ratio and 81% yield (Scheme 2).
To evaluate the impact of the aldehyde on the selectivity
of the reaction, we tested a collection of electronically diverse
aldehydes with varying steric demands (Scheme 2). Interest-
ingly, replacement of 2,6-dichlorobenzaldehyde with the
electronically similar 2,4-dichlorobenzaldehyde resulted in
a dramatic reduction of the product ratio from greater than
25:1 to 2.6:1. Further reduction in the ratio to 1:1 was seen for
2
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
product isomerization is an important contributor to the
overall selectivity.[6m]
Outlined in Scheme 4 is a potential mechanism for the
redox-neutral a-alkynylation. Reaction of [Cu(2-EH)2] with
phenylacetylene results in the formation of [CuI-2-EH], the
Scheme 4. Proposed mechanism for a-alkynylation.
Glaser product, and one equivalent of 2-EHA [Eq. (5)]. The
active copper acetylide is formed upon reaction of [CuI-2-EH]
with phenylacetylene, with concurrent release of another
equivalent of 2-EHA [Eq. (6)]. 2-EHA is believed to play
a crucial role in the overall reaction [Eq. (7)]. Firstly, it is
expected to facilitate the formation of the iminium ion 10. As
indicated in Scheme 1, the carboxylate anion of 10 could bring
about iminium isomerization by deprotonation/reprotona-
tion. Alternatively, the N,O-acetal 11, which should exist in
equilibrium with 10, could eliminate 2-EHA by a concerted
pathway to form azomethine ylide 12.[16,20] Regioselective
protonation of the azomethine ylide 12 by 2-EHA results in
the iminium ion 13, which may exist in equilibrium with the
corresponding N,O-acetal (not shown). In the final step, 13
engages the copper acetylide to form the propargylic amine
6a, concomitant with the regeneration of [CuI-2-EH]
[Eq. (8)]. Although [Cu(2-EH)2] is the only additive, the
two active catalysts [CuI-2-EH] and 2-EHA are formed in situ
and activate both reaction partners separately in what may be
considered an example of synergistic catalysis.[21]
To demonstrate the utility of the propargylic amines
derived from the redox-neutral a-alkynylation, a number of
products were selectively transformed. Debenzylation of 8a
with simultaneous reduction of the triple bond was accom-
plished by transfer hydrogenation to provide the product 14
[Eq. (9)]. This approach can also be employed to remove the
undesired regioisomer in cases where the alkynylation is less
regioselective. For instance, exposure of a 1.2:1 mixture of 8t
and 9t to the transfer hydrogenation conditions led to clean
formation of morpholine 15 [Eq. (10)]. An alternative two-
step debenzylation strategy designed to preserve the alkyne
functionality allowed the synthesis of the propargylamine 16
[Eq. (11)].
Scheme 3. Scope of the direct a-alkynylation. Ar=2,6-Cl2C6H3.
a synthetically useful range. Morpholine provided only small
amounts of desired regioisomer in a reaction with phenyl-
acetylene. Interestingly, the introduction of an ortho-methyl
substituent to phenylacetylene allowed the isolation of 8t and
9t in a 1.2:1 ratio. Finally, although alkynylation products
from acyclic amines are available by traditional A3 chemistry,
we decided to test N-methylbenzylamine under the standard
reaction conditions. In the event, the products 8u and 9u were
isolated in a 4:1 ratio, albeit in only 35% yield.
To establish whether the regioselectivity of the alkynyla-
tion could be affected by product isomerization, we exposed
7a to the reaction conditions.[19] To best mimic the original
reaction conditions, phenylacetylene, pyrrolidine and water
were added [Eq. (4)]. Very little isomerization was observed
in addition to the formation of 1,4-diphenylbuta-1,3-diyne,
and 6a and 7a were recovered in a 1:6 ratio (87% yield).
While this study establishes the potential reversibility of the
reaction, the degree of isomerization is insufficient to account
for the observed regioselectivity of the parent reaction.
Therefore, the product ratios likely reflect the intrinsic
reactivities of the reaction intermediates. This is in stark
contrast to our previous study on a-cyanation in which
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Landers, O. Navarro, Org. Biomol. Chem. 2012, 10, 2206; f) C. E.
Meyet, C. J. Pierce, C. H. Larsen, Org. Lett. 2012, 14, 964;
g) B. R. Buckley, A. N. Khan, H. Heaney, Chem. Eur. J. 2012, 18,
3855; h) C. J. Pierce, M. Nguyen, C. H. Larsen, Angew. Chem.
2012, 124, 12455; Angew. Chem. Int. Ed. 2012, 51, 12289.
[5] a) N. Z. Burns, P. S. Baran, R. W. Hoffmann, Angew. Chem.
2009, 121, 2896; Angew. Chem. Int. Ed. 2009, 48, 2854; b) T.
Newhouse, P. S. Baran, R. W. Hoffmann, Chem. Soc. Rev. 2009,
38, 3010.
[6] a) C. Zhang, C. K. De, R. Mal, D. Seidel, J. Am. Chem. Soc. 2008,
130, 416; b) S. Murarka, C. Zhang, M. D. Konieczynska, D.
Seidel, Org. Lett. 2009, 11, 129; c) C. Zhang, S. Murarka, D.
Seidel, J. Org. Chem. 2009, 74, 419; d) S. Murarka, I. Deb, C.
Zhang, D. Seidel, J. Am. Chem. Soc. 2009, 131, 13226; e) C.
Zhang, D. Seidel, J. Am. Chem. Soc. 2010, 132, 1798; f) I. Deb, D.
Seidel, Tetrahedron Lett. 2010, 51, 2945; g) C. Zhang, D. Das, D.
Seidel, Chem. Sci. 2011, 2, 233; h) I. Deb, D. Das, D. Seidel, Org.
Lett. 2011, 13, 812; i) M. C. Haibach, I. Deb, C. K. De, D. Seidel,
J. Am. Chem. Soc. 2011, 133, 2100; j) I. Deb, D. Coiro, D. Seidel,
Chem. Commun. 2011, 47, 6473; k) M. K. Vecchione, A. X. Sun,
D. Seidel, Chem. Sci. 2011, 2, 2178; l) D. Das, M. T. Richers, L.
Ma, D. Seidel, Org. Lett. 2011, 13, 6584; m) L. Ma, W. Chen, D.
Seidel, J. Am. Chem. Soc. 2012, 134, 15305.
In summary, we have developed an unprecedented
approach for the one-step synthesis of ring-substituted
propargylic amines. The combination of a reductive amine
N-alkylation with an oxidative a-functionalization effectively
renders this process redox-neutral. We anticipate wide
adoption of this concept as a means to rapidly access a-
functionalized amines from simple precursors.
[7] H.-P. Bi, Q. Teng, M. Guan, W.-W. Chen, Y.-M. Liang, X. Yao,
C.-J. Li, J. Org. Chem. 2010, 75, 783.
Experimental Section
General procedure: A 10 mL microwave reaction tube was charged
with a 10 ꢀ 8 mm SiC passive heating element, copper(II) 2-ethyl-
hexanoate (0.038 mmol, 0.15 equiv), toluene (1 mL), alkyne
(0.375 mmol, 1.5 equiv), amine (0.375 mmol, 1.5 equiv) and aldehyde
(0.25 mmol). The reaction tube was sealed with a Teflon-lined snap
cap, and heated in a microwave reactor at 1508C (200 W, 30–80 psi)
for 15 min. [Note: SiC passive heating elements must not be used in
conjunction with stir bars for they may score glass and cause vessel
failure.] After cooling with compressed air flow, the reaction mixture
was directly loaded onto a column and purified by silica gel
chromatography.
[8] For an oxidative variant, see: H.-P. Bi, L. Zhao, Y.-M. Liang, C.-
J. Li, Angew. Chem. 2009, 121, 806; Angew. Chem. Int. Ed. 2009,
48, 792.
[9] Decarboxylative A3 reactions: a) H. Feng, D. S. Ermolatꢁev, G.
Song, E. V. Van der Eycken, J. Org. Chem. 2011, 76, 7608; b) H.
Feng, D. S. Ermolatꢁev, G. Song, E. V. Van der Eycken, Org.
Lett. 2012, 14, 1942; c) H. Feng, D. S. Ermolatꢁev, G. Song, E. V.
Van der Eycken, J. Org. Chem. 2012, 77, 5149.
[10] Selected reviews on amine a-functionalization: a) S. I. Muraha-
shi, Angew. Chem. 1995, 107, 2670; Angew. Chem. Int. Ed. Engl.
1995, 34, 2443; b) S. Doye, Angew. Chem. 2001, 113, 3455;
Angew. Chem. Int. Ed. 2001, 40, 3351; c) K. R. Campos, Chem.
Soc. Rev. 2007, 36, 1069; d) S. I. Murahashi, D. Zhang, Chem.
Soc. Rev. 2008, 37, 1490; e) C.-J. Li, Acc. Chem. Res. 2009, 42,
335; f) W. J. Yoo, C.-J. Li, Top. Curr. Chem. 2010, 292, 281; g) R.
Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer, O. Baudoin,
Chem. Eur. J. 2010, 16, 2654; h) C. S. Yeung, V. M. Dong, Chem.
Rev. 2011, 111, 1215; i) C. L. Sun, B. J. Li, Z. J. Shi, Chem. Rev.
2011, 111, 1293; j) C. Liu, H. Zhang, W. Shi, A. W. Lei, Chem.
Rev. 2011, 111, 1780; k) A. E. Wendlandt, A. M. Suess, S. S.
Stahl, Angew. Chem. 2011, 123, 11256; Angew. Chem. Int. Ed.
2011, 50, 11062; l) K. M. Jones, M. Klussmann, Synlett 2012, 159;
m) C. Zhang, C. H. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3464;
n) E. A. Mitchell, A. Peschiulli, N. Lefevre, L. Meerpoel,
B. U. W. Maes, Chem. Eur. J. 2012, 18, 10092; o) L. Shi, W.
Xia, Chem. Soc. Rev. 2012, 41, 7687.
[11] Selected articles on oxidative amine a-alkynylation: a) Z. Li, C.-
J. Li, J. Am. Chem. Soc. 2004, 126, 11810; b) Z. Li, C.-J. Li, Org.
Lett. 2004, 6, 4997; c) Z. Li, P. D. MacLeod, C.-J. Li, Tetrahedron:
Asymmetry 2006, 17, 590; d) S. Turcaud, E. Sierecki, T. Martens,
J. Royer, J. Org. Chem. 2007, 72, 4882; e) M. Niu, Z. Yin, H. Fu,
Y. Jiang, Y. Zhao, J. Org. Chem. 2008, 73, 3961; f) L. Zhao, C.-J.
Li, Angew. Chem. 2008, 120, 7183; Angew. Chem. Int. Ed. 2008,
47, 7075; g) X. L. Xu, X. N. Li, Org. Lett. 2009, 11, 1027;
h) C. M. R. Volla, P. Vogel, Org. Lett. 2009, 11, 1701; i) P. Liu,
C. Y. Zhou, S. Xiang, C. M. Che, Chem. Commun. 2010, 46, 2739;
j) W. K. Su, J. B. Yu, Z. H. Li, Z. J. Jiang, J. Org. Chem. 2011, 76,
9144; k) E. Boess, C. Schmitz, M. Klussmann, J. Am. Chem. Soc.
2012, 134, 5317; l) K. N. Singh, P. Singh, A. Kaur, Synlett 2012,
760.
Received: January 2, 2013
Published online: && &&, &&&&
À
Keywords: azomethine ylides · C H activation · copper ·
heterocycles · microwave chemistry
.
[1] See: P. de Armas, D. Tejedor, F. Garcia-Tellado, Angew. Chem.
2010, 122, 1029; Angew. Chem. Int. Ed. 2010, 49, 1013, and
references therein.
[2] A3 reactions: selected key contributions: a) A. B. Dyatkin, R. A.
Rivero, Tetrahedron Lett. 1998, 39, 3647; b) G. W. Kabalka, L.
Wang, R. M. Pagni, Synlett 2001, 676; c) C.-J. Li, C. M. Wei,
Chem. Commun. 2002, 268; d) C. M. Wei, C.-J. Li, J. Am. Chem.
Soc. 2003, 125, 9584; e) N. Gommermann, C. Koradin, K.
Polborn, P. Knochel, Angew. Chem. 2003, 115, 5941; Angew.
Chem. Int. Ed. 2003, 42, 5763.
[3] A3 reactions: selected reviews: a) C. Wei, Z. Li, C.-J. Li, Synlett
2004, 1472; b) L. Zani, C. Bolm, Chem. Commun. 2006, 4263;
c) V. V. Kouznetsov, L. Y. V. Mendez, Synthesis 2008, 491;
d) W. J. Yoo, L. Zhao, C.-J. Li, Aldrichimica Acta 2011, 44, 43;
e) V. A. Peshkov, O. P. Pereshivko, E. V. Van der Eycken, Chem.
Soc. Rev. 2012, 41, 3790.
[4] A3 reactions: selected recent contributions: a) T. A. Graf, T. K.
Anderson, N. B. Bowden, Adv. Synth. Catal. 2011, 353, 1033;
b) M. Cheng, Q. Zhang, X. Y. Hu, B. G. Li, J. X. Ji, A. S. C.
Chan, Adv. Synth. Catal. 2011, 353, 1274; c) S. S. Patil, S. V. Patil,
V. D. Bobade, Synlett 2011, 1157; d) M. Saifuddin, P. K. Agarwal,
B. Kundu, J. Org. Chem. 2011, 76, 10122; e) M. T. Chen, B.
[12] Photoredox approaches to amine a-alkynylation: a) D. B. Free-
man, L. Furst, A. G. Condie, C. R. Stephenson, Org. Lett. 2012,
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
14, 94; b) M. Rueping, R. M. Koenigs, K. Poscharny, D. C. Fabry,
D. Leonori, C. Vila, Chem. Eur. J. 2012, 18, 5170.
Waetzig, J. A. Tunge, J. Am. Chem. Soc. 2009, 131, 16626;
k) V. K.-Y. Lo, C.-Y. Zhou, M.-K. Wong, C.-M. Che, Chem.
Commun. 2010, 46, 213; l) J. Kuang, S. Ma, J. Am. Chem. Soc.
2010, 132, 1786; m) Y. K. Kang, S. M. Kim, D. Y. Kim, J. Am.
Chem. Soc. 2010, 132, 11847; n) P. Dunkel, G. Turos, A. Benyei,
K. Ludanyi, P. Matyus, Tetrahedron 2010, 66, 2331; o) G. Zhou, J.
Zhang, Chem. Commun. 2010, 46, 6593; p) H. Mao, R. Xu, J.
Wan, Z. Jiang, C. Sun, Y. Pan, Chem. Eur. J. 2010, 16, 13352;
q) W. D. Cao, X. H. Liu, W. T. Wang, L. L. Lin, X. M. Feng, Org.
Lett. 2011, 13, 600; r) G. H. Zhou, F. Liu, J. L. Zhang, Chem. Eur.
J. 2011, 17, 3101; s) N. Ghavtadze, R. Narayan, B. Wibbeling,
E. U. Wuerthwein, J. Org. Chem. 2011, 76, 5185; t) K. Mori, K.
Ehara, K. Kurihara, T. Akiyama, J. Am. Chem. Soc. 2011, 133,
6166; u) Y. P. He, Y. L. Du, S. W. Luo, L. Z. Gong, Tetrahedron
Lett. 2011, 52, 7064; v) S. J. Mahoney, E. Fillion, Chem. Eur. J.
2012, 18, 68; w) I. D. Jurberg, B. Peng, E. Woestefeld, M.
Wasserloos, N. Maulide, Angew. Chem. 2012, 124, 1986; Angew.
Chem. Int. Ed. 2012, 51, 1950; x) Y. Y. Han, W. Y. Han, X. Hou,
X. M. Zhang, W. C. Yuan, Org. Lett. 2012, 14, 4054; y) L. J.
Chen, L. Zhang, J. Lv, J. P. Cheng, S. Z. Luo, Chem. Eur. J. 2012,
18, 8891.
[13] For conceptually different a-alkynylations of tertiary amines,
see: T. Sugiishi, H. Nakamura, J. Am. Chem. Soc. 2012, 134, 2504.
[14] For iridium-catalyzed a-alkenylations of imines with alkynes,
see: S. Sakaguchi, T. Kubo, Y. Ishii, Angew. Chem. 2001, 113,
2602; Angew. Chem. Int. Ed. 2001, 40, 2534.
[15] R. Huisgen, R. Grashey, E. Steingruber, Tetrahedron Lett. 1963,
4, 1441.
[16] Selected reviews on azomethine ylides: a) A. Padwa, W. H.
Pearson, Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products, Vol. 59,
Wiley, Chichester, 2002; b) C. Najera, J. M. Sansano, Curr. Org.
Chem. 2003, 7, 1105; c) I. Coldham, R. Hufton, Chem. Rev. 2005,
105, 2765; d) G. Pandey, P. Banerjee, S. R. Gadre, Chem. Rev.
2006, 106, 4484; e) T. M. V. D. Pinho e Melo, Eur. J. Org. Chem.
2006, 2873; f) C. Nꢂjera, J. M. Sansano, Top. Heterocycl. Chem.
2008, 12, 117; g) M. Nyerges, J. Toth, P. W. Groundwater, Synlett
2008, 1269; h) J. Adrio, J. C. Carretero, Chem. Commun. 2011,
47, 6784.
[17] Selected recent articles on redox-neutral amine functionaliza-
tion: a) S. J. Pastine, K. M. McQuaid, D. Sames, J. Am. Chem.
Soc. 2005, 127, 12180; b) M. Tobisu, N. Chatani, Angew. Chem.
2006, 118, 1713; Angew. Chem. Int. Ed. 2006, 45, 1683; c) P.
Mꢂtyus, O. ꢃliꢂs, P. Tapolcsꢂnyi, A. Polonka-Bꢂlint, B. Halꢂsz-
Dajka, Synthesis 2006, 2625; d) M. Oda, Y. Fukuchi, S. Ito, N. C.
Thanh, S. Kuroda, Tetrahedron Lett. 2007, 48, 9159; e) L. Zheng,
F. Yang, Q. Dang, X. Bai, Org. Lett. 2008, 10, 889; f) J.
Barluenga, M. Fananas-Mastral, F. Aznar, C. Valdes, Angew.
Chem. 2008, 120, 6696; Angew. Chem. Int. Ed. 2008, 47, 6594;
g) K. Mori, Y. Ohshima, K. Ehara, T. Akiyama, Chem. Lett.
2009, 38, 524; h) L. Cui, Y. Peng, L. Zhang, J. Am. Chem. Soc.
2009, 131, 8394; i) P. A. Vadola, D. Sames, J. Am. Chem. Soc.
2009, 131, 16525; j) N. K. Pahadi, M. Paley, R. Jana, S. R.
[18] a) C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422; b) P. Siemsen,
R. C. Livingston, F. Diederich, Angew. Chem. 2000, 112, 2740;
Angew. Chem. Int. Ed. 2000, 39, 2632.
[19] Reversibility in an iminium alkynylation has previously been
demonstrated: T. Sugiishi, A. Kimura, H. Nakamura, J. Am.
Chem. Soc. 2010, 132, 5332.
[20] This mode of azomethine ylide formation from a carboxylic acid
derived N,O-acetal was proposed by Yu et al. as part of
a computational investigation of Tungeꢁs benzoic acid catalyzed
synthesis of N-alkyl pyrroles from 3-pyrroline: X. S. Xue, A. Yu,
Y. Cai, J. P. Cheng, Org. Lett. 2011, 13, 6054. See also
reference [17j].
[21] A. E. Allen, D. W. C. MacMillan, Chem. Sci. 2012, 3, 633.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
À
C H Functionalization
D. Das, A. X. Sun,
D. Seidel*
&&&& — &&&&
Redox-Neutral Copper(II) Carboxylate
Catalyzed a-Alkynylation of Amines
Cocktail of three: A new strategy for
iminium ion isomerization was applied to
the direct, redox-neutral a-alkynylation of
amines. Copper(II) 2-ethylhexanoate [Cu-
(2-EH)2] was identified as the optimal
catalyst for this three-component cou-
pling reaction of secondary amines,
aldehydes, and alkynes. MW=micro-
wave.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!