Copper(I)-catalyzed deacetylenative coupling of propargylic amines: An efficient synthesis of symmetric 1,4-diamino-2-butynes

Article abstract of DOI:10.1002/chem.201102710

Deacetylenative coupling: Propargylic amines undergo copper-catalyzed deacetylenative coupling to give the symmetric 1,4-diamino-2-butynes. In the presence of a base, the Glaser-type homocoupling takes place, whereas in the absence of a base the deacetylenative coupling takes place (see scheme).

Full text of DOI:10.1002/chem.201102710

COMMUNICATION
DOI: 10.1002/chem.201102710
Copper(I)-Catalyzed Deacetylenative Coupling of Propargylic Amines:
An Efficient Synthesis of Symmetric 1,4-Diamino-2-butynes
Yongeun Kim and Hiroyuki Nakamura*[a]
Copper-catalyzed homocoupling reactions of terminal al-
kynes, known as the Glaser–Hay coupling reaction, are well-
established process for the synthesis of symmetric 1,3-diynes
(e.g., path A in Scheme 1).[1–3] Catalytic systems involving
We first examined the effects of various copper catalysts
on the deacetylenative coupling reaction of propargylic
amine 1a.[15] The results are shown in Table 1. The reaction
Table 1. Optimization of the reaction conditions for the deacetylenative
coupling of propargylic amine 1a.[a]
Entry
Catalyst (mol%)
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
CuCl (10)
CuCl (20)
CuCl (10)
CuCl (20)
CuBr (10)
CuOAc (10)
100
100
130
130
100
100
100
59 (27)
59 (30)
90
86
13 (83)
trace (89)
trace (77)
CuACTHNUTRGEN(NUG OTf)2 (10)
Scheme 1. Copper-catalyzed reaction pathways of propargylic amines.
[a] Reaction conditions: propargylic amine 1 (0.3 mmol) was treated with
Cu catalyst (0.03 or 0.06 mmol) in THF (1.2 mL) under N2 atmosphere in
a vial tube. [b] Yield of product isolated after silica gel chromatography.
Recovery of 1a is indicated in the parenthesis. Bn=benzyl.
palladium, Pd0 or PdII, are also efficient and selective for the
oxidative homocoupling reactions of terminal alkynes.[4] Not
only homocoupling reactions, but also cross-coupling reac-
tions of different terminal alkynes have been developed for
the synthesis of unsymmetric 1,3-diynes.[5–8] Both symmetric
and unsymmetric 1,3-diynes are important building blocks
for the construction of linearly conjugated acetylenic p sys-
tems,[9] natural products,[10] and pharmaceuticals.[11] In gener-
al, the Glaser–Hay reaction and the related deprotonative
dimerizations proceed in the presence of amines and
oxygen, as bases and the terminal oxidant, respectively.[12]
In this paper, we report a copper-catalyzed deacetylena-
tive homocoupling reaction of propargylic amines (path B in
Scheme 1). In this transformation, an acetylenic moiety of
propargylic amines 1 is eliminated during the homocoupling
process, and the corresponding symmetric 1,4-diamino-2-bu-
tynes 3 were obtained in good yields. To the best of our
knowledge, only a few procedures have been reported for
the synthesis of 1,4-disubstituted 1,4-diamino-2-butynes.[13–15]
of N,N-dibenzyl-5-methyl-1-hexyn-3-amine (1a) proceeded
in the presence of CuCl (10 mol%) in THF at 1008C for
24 h to give the deacetylenative coupling product 3a in 59%
yield along with 27% recovery of 1a (Table 1, entry 1). In-
creasing the amount of CuCl catalyst to 20 mol% did not
affect the yield of 3a (Table 1, entry 2). However, carrying
out the reaction at a higher temperature is effective; com-
pound 3a was obtained in 90% (10 mol% CuCl, Table 1,
entry 3) and 86% (20 mol% CuCl, entry 4) yields, when the
reaction was carried out at 1308C. Other copper(I) catalysts,
CuBr and CuOAc, and a copper(II) catalyst, CuACHTUNGTRENNUNG(OTf)2
(Tf=trifluoromethanesulfonate), were not efficient for this
reaction (Table 1, entries 5–7).
We also examined solvent effects for this deacetylenative
coupling reaction in the presence of CuCl (10 mol%) using
various solvents including toluene, dioxane, dichloroethane,
DMF, acetonitrile, methoxycyclopentane, and cyclohexane.
Although the deacetylenative coupling product 3a was ob-
tained predominantly, yields were lower (4–42%) in all
cases (Table S1 in the Supporting Information). We next ex-
amined the role of amine bases in the copper-catalyzed cou-
pling reactions. As shown in Table 2, addition of 4-dimethyl-
aminopyridine (DMAP) increased the generation of the
Glaser–Hay-type homocoupling product 2a. When more
[a] Dr. Y. Kim, Prof. Dr. H. Nakamura
Department of Chemistry
Faculty of Science, Gakushuin University
1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588 (Japan)
Fax : (+81)3-5992-1029
E-mail: hiroyuki.nakamura@gakushuin.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102710.
Chem. Eur. J. 2011, 17, 12561 – 12563
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12561

Table 2. Effect of DMAP on the coupling reaction.
Table 3. CuCl-catalyzed deacetylenative coupling of propargylic amine
derivatives.[a]
Entry
1[c]
1
Product 3
Yield [%][b]
90
1a
3a
Entry
DMAP (equiv)
Total Yield [%][a]
Ratio [2a/3a][b]
2
3
4
1b
1c
1d
3b
3c
3d
60
51
45
1
2
3
4
5
0
59 (27)
42 (56)
24 (60)
54 (37)
86 (0)
0:10
3:7
3:7
10:0
10:0
0.1
0.5
1
2
[a] Total yield of products 2a and 3a isolated after silica gel chromatog-
raphy. Recovery of 1a is indicated in the parenthesis. [b] Product ratios
were determined by H NMR spectroscopy.
1
than one equivalent of DMAP was employed for the reac-
tion, compound 2a was obtained predominantly (Table 2,
entries 4 and 5). Not only DMAP, but also other bases in-
cluding 2,2’-bipyridine, Cs2CO3, and Na2HPO4 afforded 2a
as the major product (Table S2 in the Supporting Informa-
tion). With optimized conditions established, we next inves-
tigated the deacetylenative coupling reaction with various
propargylic amines. The results are summarized in Table 3.
The reaction was performed in the presence of CuCl catalyst
(20 mol%) at 1308C without a base. Under this reaction
condition, the isobutyl-substituted (R1 =iBu) propargylic
amines, such as dibenzyl- (1a), dihexyl- (1b), diallyl- (1c),
dicyclohexyl- (1d), and N-ethylbenzyl- (1e) underwent the
deacetylenative coupling reaction to give the corresponding
1,4-diamino-2,9-dimethyl-5-decynes (3a–3e) in moderate to
good yields (Table 3, entries 1–5). However, N,N-dibenzyl-
prop-2-yn-1-amine (1 f) gave the corresponding product 3 f
in 37% yield (Table 3, entry 6). These results indicate that
the substituents at a propargylic position are efficient for
the deacetylenative coupling reaction. A variety of substitut-
ed propargylic N,N-dibenzylamines, such as n-pentyl- (1g),
isopropyl- (1h), cyclohexyl- (1i), and phenethyl- (1j), were
employed in the deacetylative coupling reaction to afford
the corresponding symmetric 1,4-diamino-2-butynes (3g–j)
in 63–84% yields (Table 3, entries 7–10). The deacetylena-
tive coupling reaction was also applied to aromatic substitut-
ed propargylic N,N-dibenzylamines, such as phenyl-
(Table 3, entry 11), 1-naphthyl- (entry 12), and 3-furanyl-
(entry 13). In all cases, the Glaser–Hay-type homocoupling
products were not detected.
5
1e
3e
73
6
7
1 f
1g
3 f
3g
37
84
8
9
1h
1i
3h
3i
63[d]
75
10
11
1j
3j
72
41
1k
3k
12
13
1l
3l
44
1m
3m
39[e]
A mechanistic rationale, which accounts for the unprece-
dented deacetylenative coupling reaction of propargylic
amines, is shown in Scheme 2. Propargylic amines 1 would
À
undergo the C(sp) CACTHNUTRGNEUNG
(sp3) bond cleavage by CuCl to gener-
[a] Reaction conditions: propargylic amine 1 (0.3 mmol) was treated with
CuCl (0.06 mmol) in THF (1.2 mL) at 1308C under N2 atmosphere in a
sealed vial tube. [b] Yield of product isolated after silica gel chromatogra-
phy. [c] With 0.03 mmol of CuCl. [d] Recovery of 1h (7%) was observed.
[e] Recovery of 1m (14%) was observed.
ate the iminium intermediate 4 and a copper acetylide 5,
which reacts with another propargylic amine 1 to afford the
corresponding propargylic acetylide 6 and an acetylene. Ad-
dition of 6 to the iminium intermediate 4 would give the de-
12562
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 12561 – 12563

Copper(I)-Catalyzed Deacetylenative Coupling
COMMUNICATION
with hexane and ethyl acetate as eluent to give 3a as a white solid
(75 mg, 90% yield). In a similar manner, compounds 3b–3m were pre-
pared from the corresponding propargylic amines 1b–1m in 37–84%
yields.
Acknowledgements
Y.K. thanks the Japan Society for the Promotion of Science (JSPS, ID
No. P09240) for financial support.
Scheme 2. Plausible mechanism.
Keywords: alkynes · amines · copper · deacetylenative
coupling · synthetic methods
acetylenative coupling product 3 with the regeneration of
CuCl. Recently, we reported the copper(I)-catalyzed substi-
tution reactions of propargylic amines.[16] In this transforma-
À
[1] a) C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422–424; b) C. Glaser,
Justus Liebigs Ann. Chem. 1870, 154, 137–171; c) P. Siemsen, R. C.
Livingston, F. Diederich, Angew. Chem. 2000, 112, 2740–2767;
Angew. Chem. Int. Ed. 2000, 39, 2632–2657.
[2] G. Eglinton, R. Galbraith, J. Chem. Soc. 1959, 889–896.
[3] A. S. Hay, J. Org. Chem. 1962, 27, 3320–3323.
[4] E. Negishi, A. Alimardanov in Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. 1 (Ed.: E. Negishi), Wiley-In-
terscience, New York, 2002, p. 989.
[5] a) W. Chodkiewicz, P. Cadiot, C. R. Hebd. Seances Acad. Sci. 1955,
241, 1055–1057; b) W. Chodkiewicz, Ann. Chim. (Paris) 1957, 2,
819–869.
tion, the C(sp) CACHTUNGTRENNUNG
(sp3) bond cleavage step is essential for
the generation of the copper acetylide and iminium inter-
mediates, which undergo fragment exchange with additional
aldehydes, amines, and alkynes to give the corresponding
À
propargylic amines. Therefore, the C(sp) CACTHNUTRGNEUNG
(sp3) bond cleav-
age assisted by the nitrogen lone-pair electrons is essential
for the current deacetylenative coupling reaction prior to
the Glaser–Hay homocoupling reaction.
In conclusion, we have developed the deacetylenative
coupling reaction from two alkyne fragment exchange reac-
tions between terminal propargylic amines in the presence
of copper(I) catalysts. The mere presence or absence of
bases suffices to control the reactivity of propargylic amines.
In the presence of bases, the Glaser-type homocoupling re-
action takes place, whereas in the absence of bases the de-
acetylenative coupling reaction takes place. Now we can
prepare both 1,4-diamino-2-butynes and 1,6-diamino-1,3-
diynes selectively from the same propargylic amines.
[6] Y. Nishihara, K. Ikegashira, A. Mori, T. Hiyama, Tetrahedron Lett.
1998, 39, 4075–4078.
[7] R. Rossi, A. Carpita, C. Bigelli, Tetrahedron Lett. 1985, 26, 523–526.
[8] J. Wityak, J. B. Chan, Synth. Commun. 1991, 21, 977–979.
[9] a) J. M. Tour, Chem. Rev. 1996, 96, 537–554; b) R. E. Martin, F. Die-
derich, Angew. Chem. 1999, 111, 1440–1469; Angew. Chem. Int. Ed.
1999, 38, 1350–1377.
[10] A. L. K. Shi Shun, R. R. Tykwinski, Angew. Chem. 2006, 118, 1050–
1073; Angew. Chem. Int. Ed. 2006, 45, 1034–1057.
[11] a) D. Elbaum, T. B. Nguyen, W. L. Jorgensen, S. L. Schreiber, Tetra-
hedron 1994, 50, 1503–1518; b) J.-P. Gotteland, I. Brunel, F. Gendre,
J. Desire, A. Delhon, D. Junquero, P. Oms, J. Halazy, J. Med. Chem.
1995, 38, 3207–3216.
[12] H.-Q. Do, O. Daugulis, J. Am. Chem. Soc. 2009, 131, 17052–17053.
[13] K. Banert, Tetrahedron Lett. 1985, 26, 5261–5264.
[14] G. Courtois, V. Desrꢁ, L. Miginiac, J. Organomet. Chem. 1999, 580,
178–187.
[15] N. Gommermann, P. Knochel, Chem. Eur. J. 2006, 12, 4380–4392.
[16] T. Sugiishi, A. Kimura, H. Nakamura, J. Am. Chem. Soc. 2010, 132,
5332–5333.
Experimental Section
CuCl (3 mg, 0.03 mmol) was added to a mixture of N,N-dibenzyl-5-meth-
ylhex-1-yn-3-amine (1a, 87 mg, 0.3 mmol) in THF (1.2 mL) in a sealed
vial tube under N2, and the mixture was stirred at 1308C for 24 h. After
the insoluble materials were removed by filtration through a pad of
Celite and washed with diethyl ether, the filtrate was concentrated in
vacuo. The residue was purified by column chromatography on silica gel
Received: August 30, 2011
Published online: September 29, 2011
Chem. Eur. J. 2011, 17, 12561 – 12563
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12563